Textbook of Natural Medicine - 2-volume set [5th Edition] 0323523420, 9780323523424, 9780323523790

Table of contents :
SECTION I: PHILOSOPHY OF NATURAL MEDICINE
1. Functional Medicine: A 21st Century Model of Patient Care and Medical Education
2. A Hierarchy of Healing: The Therapeutic Order
3. History of Naturopathic Medicine
4. History of Naturopathic Medicine Part 2
5. Philosophy of Naturopathic Medicine
6. Placebo and the Power to Heal
7. Positive Mental Attitude
SECTION II: SUPPLEMENTARY DIAGNOSTIC PROCEDURES
8. Apoptosis in Health and Disease
9. Bacterial Overgrowth of the Small Intestine Breath Test
10. Cell Signaling Analysis
11. Erythrocyte Sedimentation Rate
12. Fantus Test
13. Fatty Acid Profiling
14. Food Allergies
15. Genomics, Nutrigenomics, and the Promise of Personalized Medicine
16. Hair Mineral Analysis
17. Heidelberg pH Capsule Gastric Analysis
18. Immune Function Assessment
19. Intestinal Permeability Assessment
20. Laboratory Tests for the Determination of Vitamin Status
21. Lactose Intolerance Testing
22. Metal Toxicity: Assessment of Exposure and Retention
23. Mineral Status Evaluation
24. Mold Exposure Assessment
25. Non Metallic Toxic Chemical Assessment
26. Oral Manifestations of Nutritional Status
27. Rapid Dark Adaptation Test
28. Stool Analysis
29. Urinary Organic Acids Profiling for Assessment of Functional Nutrient Deficiencies, Gut Dysbiosis, and Toxicity
30. Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure
31. Urine Indican Test (Obermeyer Test)
SECTION III: THERAPEUTIC MODALITIES
32. Acupuncture
33. Ayurveda: The Science of Life and Mother of the Healing Arts
34. Botanical Medicine – A Modern Perspective
35. Environmental Medicine
36. The Exercise Prescription
37. Fasting
38. Glandular Therapy
39. Homeopathy
40. Hydrotherapy
41. Manipulation
42. Nonpharmacological Control of Pain
43. Nontransfusion Significance of ABO and ABO-Associated Polymorphisms
44. Nutritional Medicine
45. Peat Therapeutics and Balneotherapy
46. Rotation Diet: A Diagnostic and Therapeutic Tool
47. Soft Tissue Manipulation: Diagnostic and Therapeutic Potential
48. Spirituality and Healing
49. Unani Medicine
SECTION IV: PHARMACOLOGY OF NATURAL MEDICINES
50. Allium cepa (Onion)
51. Allium sativum (Garlic)
52. Aloe vera (Cape Aloe)
53. Angelica Species
54. Artemisia absinthium (Wormwood)
55. Artemisia annua (Sweet Wormwood)
56. Bee Products – Pollen, Propolis, and Royal Jelly
57. Beta-carotene and Related Carotenoids
58. Boron
59. Bromelain
60. Camellia sinensis (Green Tea)
61. Cannabis sativa, THC, and Cannabidiols
62. Capsicum frutescens (Cayenne Pepper)
63. Carnitine
64. Centella asiatica (Gotu Kola)
65. Chinese Prepared Medicines
66. Cimicifuga racemosa (Black Cohosh) John Nowicki and Michael T. Murray
67. Citicoline (CDP-Choline)
68. Coenzyme Q10
69. Coleus forskohlii
70. Commiphora mukul (Mukul Myrhh Tree)
71. Crataegus oxyacantha (Hawthorn)
72. Croton lechleri (Dragon's Blood)
73. Curcuma longa (Turmeric)
74. Dehydroepiandrosterone (DHEA)
75. Echinacea Species (Narrow-Leafed Purple Coneflower)
76. Eleutherococcus senticosus (Siberian Ginseng)
77. Ephedra Species
78. Epilobium Species (Fireweed)
79. Fatty Acid Metabolism
80. Fish Oils and Omega-3 Fatty Acids
81. Flavonoids – Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides
82. Ginkgo biloba (Ginkgo Tree)
83. Glucosamine
84. Glutamine
85. Glycyrrhiza glabra (Licorice)
86. Hydrastis canadensis (Goldenseal) and Other Berberine-Containing Botanicals
87. 5-Hydroxytryptophan
88. Hypericum perforatum (St John's Wort)
89. Lobelia inflata (Indian Tobacco)
90. Medicinal Mushroom
91. Melaleuca alternifolia (Tea Tree)
92. Melatonin
93. Melissa officinalis (Lemon Balm)
94. Mentha piperita (Peppermint)
95. Microbial Enzyme Therapy
96. Natural Medicines Quality Control
97. Naturally Occurring Antioxidants
98. Opuntia Species (Prickly Pear)
99. Panax ginseng (Korean Ginseng)
100. Pancreatic Enzymes
101. Phage Therapy: Bacteriophages as Natural, Self-limiting Antibiotics
102. Phosphatidylserine
103. Piper methisticum (Kava)
104. Prebiotics
105. Probiotics
106. Procyanidolic Oligomers
107. Pygeum africanum (Bitter Almond)
108. Pyroloquinoline quinone (PQQ)
109. Ruscus aculeatus (Butcher's Broom)
110. SAMe (S-Adenosylmethionine)
111. Sarsparilla Species
112. Serenoa repens (Saw Palmetto)
113. Silybum marianum (Milk Thistle)
114. Soy Isoflavones and Other Constituents
115. Tabebuia avellanedae (LaPacho, Pau D'Arco, Ipe Roxo)
116. Tanacetum parthenium (Feverfew)
117. Taraxacum officinale (Dandelion)
118. Taxus brevifolia (Pacific Yew)
119. Urtica dioica (Stinging Nettle)
120. Uva ursi (Bearberry)
121. Vaccinium macrocarpon (Cranberry)
122. Vaccinium myrtillus (Bilberry)
123. Valeriana officinalis (Valerian)
124. Viscum album (European Mistletoe)
125. Vitamin A
126. Vitamin K
127. Vitamin Toxicities and Therapeutic Monitoring
128. Vitex agnus castus (Chaste Tree)
129. Water: The Most Basic Nutrient and Therapeutic Agent
130. Zingiber officinale (Ginger)
SECTION V: SYNDROMES AND SPECIAL TOPICS
131. Cancer – Key Considerations in Prevention
132. Dietary Fiber
133. Digestive Support
134. Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease
135. Hyperventilation Syndrome/Breathing Pattern Disorders
136. Immune System Support
137. Let the Data Speak
138. Mycotoxins
139. Sports Nutrition
140. Stress Management
SECTION VI: SPECIFIC HEALTH PROBLEMS
141. Acne Vulgaris and Acne Conglobata
142. Affective Disorders
143. Alcohol Dependence
144. Alzheimer's Disease
145. Anemia
146. Angina
147. Aphthous Stomatitis
148. Asthma
149. Atherosclerosis
150. Atopic Dermatitis (Eczema)
151. Attention Deficit Hyperactivity Disorder in Children
152. Autism
153. Bacterial Sinusitis
154. Benign Prostatic Hyperplasia
155. Bronchitis and Pneumonia
156. Carpal Tunnel Syndrome
157. Celiac Disease
158. Cervical Dysplasia
159. Chronic Candidiasis
160. Chronic Fatigue Syndrome
161. Congestive Heart Failure
162. Constipation
163. Cystitis, Interstitial Cystitis/Painful Bladder Syndrome, and O

Citation preview

TEXTBOOK OF

Natural Medicine FIFTH EDITION EDITED BY

Joseph E. Pizzorno, ND

Editor in Chief, Integrative Medicine: A Clinician’s Journal, Eagan, Minnesota; President Emeritus, Bastyr University, Kenmore, Washington; Chair, Science Board, Bioclinical Naturals, Burnaby, British Columbia

Michael T. Murray, ND

President and CEO, Dr. Murray Natural Living, Inc., Scottsdale, Arizona; Chief Science Officer, Enzymedica, Venice, Florida

Elsevier 3251 Riverport Lane St. Louis, Missouri 63043 TEXTBOOK OF NATURAL MEDICINE, FIFTH EDITION Copyright © 2021 by Elsevier, Inc. All rights reserved. 

ISBN: 978-0-323-52342-4 Volume 1: 978-0-323-52326-4 Volume 2: 978-0-323-52325-7

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2013, 2006, 1999, and 1993. International Standard Book Number: 978-0-323-52342-4

Senior Content Strategist: Linda Woodard Senior Content Development Specialist: Rebecca Leenhouts Publishing Services Manager: Julie Eddy Book Production Specialist: Clay S. Broeker Design Direction: Margaret Reid Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

To Dr. John Bastyr and all the natural healers of the past and future who bring the “healing power of nature” to all the people of the world. Dr. Bastyr, the namesake for Bastyr University, exemplified the ideal physician/healer/teacher we endeavor to become in our professional lives. We pass on a few of his words of wisdom to all who strive to provide the best of health care and healing: “Always touch your patients—let them know you care,” and “Always read at least one research article or learn a new remedy before you retire at night.”

CONTRIBUTORS Kathy Abascal, BS, JD, RH(AHG)

Warren M. Brown, ND

Terry M. Elder, DC

Vashon, Washington

Clinical Science Liaison Medical Affairs Genova Diagnostics Asheville, North Carolina

Instructor Clinical Sciences National University of Health Sciences Lombard, Illinois

Michael J. Chapman, ND

Geovanni Espinosa, ND, LAc, IFMCP, CNS

Yaser Abdelhamid, ND, LAc, MS, BS, BA Licensed Acupuncturist Center for Integrative and Lifestyle Medicine Cleveland Clinic Cleveland, Ohio

Zemphira Alavidze, PhD

Medical Education Specialist Medical Affairs Genova Diagnostics Asheville, North Carolina

Lise Alschuler, ND

Alan G. Christianson, NMD

Professor of Clinical Medicine Assistant Director, and Fellowship in Integrative Medicine Program of Integrative Medicine University of Arizona Tucson, Arizona

President and Executive Integrative Health Scottsdale, Arizona

Anthony J. Cichoke Jr., BS, BS, MA, MA, PhD, DC, DACBN Portland, Oregon

Sidney MacDonald Baker, MD Independent Retirement Home Sag Harbor, New York

George W. Cody, JD, MA Consulting Historian Edmonds, Washington

Stephen Barrie, ND, PhD Senior Executive Viome Bellevue, Washington

David Barry, BS, BAppSci (Hons), DC, ND Clinical Research Coordinator Emeritus Research Camberwell, Victoria, Australia Senior Lecturer, Naturopathy Endeavour College of Natural Health Melbourne, Victoria, Australia

Kevin L. Conroy, ND Owner Private Practice Port Angeles Natural Health Port Angeles, West Virginia

Peter J. D’Adamo, ND, MIFHI Professor Clinical Sciences University of Bridgeport College of Naturopathic Medicine Coder/Developer Opus 23 & SWAMI

Peter W. Bennett, ND

Jade Dandy, ND, MSiMR

Clinic Director Patient Care Meditrine Naturopathic Medical Clinic Langley, British Columbia, Canada

The Healing Hut Clinic Eagle, Idaho National University of Natural Medicine Portland, Oregon

Faculty Clinical Assistant Professor NYU Langone Health, Urology Educator Institute for Functional Medicine New York, New York

Ralph Esposito, ND, LAc Adjunct Faculty New York University New York, New York

Susan Ann Gaylord, PhD Director, Program on Integrative Medicine Physical Medicine and Rehabilitation University of North Carolina (UNC) Chapel Hill, North Carolina Associate Professor Physical Medicine and Rehabilitation UNC School of Medicine Chapel Hill, North Carolina

Alan Goldhamer, DC Director Residential Health Education Program TrueNorth Health Center Santa Rosa, California Chairman of the Board Research/Education TrueNorth Health Foundation Santa Rosa, California

Andrea Gruszecki, ND Science Support Specialist Meridian Valley Laboratory Tukwilla, Washington

Bob G. Blasdel, PhD Research Director Vésale Pharma Noville-sur-Mehaigne, Belgium

Patricia M. Devers, DO

Jason A. Hawrelak, ND, BNat(Hons), PhD

Medical Education Specialist Department of Medical Affairs Genova Diagnostics, Inc.

Senior Lecturer in Complementary and Alternative Medicines College of Health & Medicine University of Tasmania Hobart, Tasmania, Australia Visiting Research Fellow Australian Research Centre for Complementary and Integrative Medicine University of Technology Sydney Sydney, New South Wales, Australia

Peter B. Bongiorno, ND, MSAc, LAc Co-Medical Director Naturopathic Medicine Inner Source Health New York, New York

Jamie Doughty, BSc, ND Medical Director Naturopathic Medicine Tummy Temple Olympia, Washington

Rachelle S. Bradley, ND Private Practice Heartland Naturopathic Clinic Omaha, Nebraska

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William Eisner, BSc Pediatrics/Cardiology Duke University Durham, North Carolina

CONTRIBUTORS

Bethany Montgomery Hays, MD

Robert Kachko, ND, LAc

Pina LoGiudice, ND, LAc

Assistant Clinical Professor Maine Medical Center Dept Ob/Gyn Tufts University School of Medicine Portland, Maine

Practitioner Naturopathic Medicine Inner Source Health New York, New York Chief Executive Officer TribeRx New York, New York

Co-Owner Innersource Natural Health and Acupuncture, PC Huntington, New York

Leah Hechtman, MSci (RHHG), BHSc (Nat), ND PhD Candidate Department of Obstetrics, Gynaecology and Neonatology | Faculty of Medicine University of Sydney Sydney, New South Wales, Australia President National Herbalists Association of Australia Sydney, New South Wales, Australia Director and Clinician The Natural Health and Fertility Centre Sydney, New South Wales, Australia

Joseph Katzinger, ND Science Director SaluGenecists Seattle, Washington

Naomi Hoyle, MD Eliava Phage Therapy Center Phage Therapy Eliava Foundation Tbilisi, Georgia

Corene Humphreys, ND, BHSc, Dip Med Herb, Dip Hom, QTA Director Nutritional Medicine

Mary James, ND Medical Editor Naturopathic Doctor News & Review Scottsdale, Arizona Expert Panel Member Women’s Health Network Portland, Maine

Chief Science Officer and Director of Quality BrainMD Health Amen Clinics Costa Mesa, California

Richard J. Kitaeff, MA, ND, Dip Ac, LAc Doctor and Clinic Director New Health Medical Center Edmonds, Washington Staff Acupuncturist Neurology Northwest Hospital Seattle, Washington Clinical Affiliate Faculty Acupuncture and Oriental Medicine Bastyr University Seattle, Washington

Cheryl Kos, ND Developer Content Personalized Medicine Lifestyle Institute Bainbridge Island, Washington

Executive Director of Medical Education Medical Education Institute for Functional Medicine Federal Way, Washington

Independent Researcher Kenmore, Washington

Helen (Verhesen) Messier Founder & Chief Medical Officer Medical Intelligence Learning Labs, Inc. San Jose, California

Steven C. Milkis, ND Owner Green Lake Natural Medicine Seattle, Washington

Gaetano Morello, ND Clinician, Complex Chronic Disease Program BC Women’s Hospital Vancouver, Canada

Gerard E. Mullin, MD Associate Professor of Medicine Gastroenterology and Hepatology Johns Hopkins School of Medicine Baltimore, Maryland

Stephen P. Myers, ND, BMed PhD

Thomas A. Kruzel, MT, ND

Professor and Director NatMed Research Unit Southern Cross University New South Wales, Australia

Rockwood Natural Medicine Clinic Scottsdale, Arizona

Toshia R. Myers, BS, MA, MPhil, PhD

Sarah Kuhl, MD, PhD

Ordained Minister United Church of Christ

Physician Medicine VA Northern California Martinez, California

Wayne Jonas, MD

Elizabeth Kutter, BS, PhD

Executive Director Samueli Integrative Health Programs H&S Ventures Alexandria, Virginia

Faculty Emeritas Bacteriophage Lab The Evergreen State College Olympia, Washington

Maeba Jonas, MDiv

Robert Luby, MD

Tennille Marx, ND, CFS Parris M. Kidd, BSc, PhD

Wendy Hodsdon, ND Adjunct Faculty Department of Graduate Studies National University of Natural Medicine Portland, Oregon Adjunct Faculty Maryland University of Integrative Health Laurel, Maryland

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Michael Alexander Lane, MD Assistant Professor Department of Neurology Oregon Health and Sciences University Portland, Oregon

Research Director Research TrueNorth Health Foundation Santa Rosa, California

Tara Nayak, ND Naturopathic Physician Philadelphia, Pennsylvania

Mark Harrison Nolting, ND, EAMP Senior Medical Director Physical Medicine TivityHealth Chandler, Arizona Medical Director Edmonds Wellness Clinic Edmonds, Washington

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CONTRIBUTORS

John Nowicki, ND

David Quig, PhD

Michael Scott, ND, MSA

Medical Writer, Research Associate Medical Research Team Integrative Medicine Advisors, LLC Seattle, Washington

Vice President Scientific Support Doctor’s Data, Inc. St. Charles, Illinois

Doctor Private Practice UrbanHealthWorks Boulder, Colorado

Brian Orr, BA, BS, ND

John C. Reed, MD, MDiv

Tracey Seipel, FANPA, ABC

Owner Country Doc: Integrative Medical Specialty Seattle, Washington

Founding VP and Fellow of the American Academy of Medical Acupuncture Fellow of the Osteopathic Cranial Academy Diplomate of the American Board of Family Medicine Diplomate of the American Board of Integrative Medicine Founding Member, American Holistic Medical Association

Fellow of the Australian Naturopathic Practitioners Association American Botanical Council Queensland, Australia

Ron Reichert, BA, ND Naturopathic Physician North Vancouver, Canada

Ann Shippy, MD

Kristaps Paddock, ND Medical Director Charm City Natural Health Baltimore, Maryland

William Shaw, PhD President Great Planes Laboratory Kansas City, Missouri

Cristiana I. Paul, MS Nutrition Independent Research Consultant Nutritional Biochemistry Research Cristiana Paul Consulting Los Angeles, California

Functional Medicine Physician Environmental Health Expert Austin, Texas

Corey Resnick, ND Nicole Pierce, ND Co-creator The Vervain Collective Garden City, Idaho

Lara Pizzorno, MAR, MA, LMT Senior Medical Writer and Editor Writing and Editorial Staff Integrative Medicine Advisors, LLC Seattle, Washington Senior Medical Editor SaluGenecists, Inc. Seattle, Washington

Terry Arden Pollock, BS, MS Medical Education Specialist Medical Affairs Genova Diagnostics Asheville, North Carolina

Dirk W. Powell, BS, ND Adjunct Professor Naturopathic Medicine Bastyr University Kent, Washington

President Integrative Health and Nutrition, Inc. Lake Oswego, Oregon Member Medical Advisory Board Integrative Therapeutics Green Bay, Wisconsin

Deceased

Clinical Assistant Professor Rusk Rehabilitation New York University Langone Medical Center New York, New York Adjunct Professor Health Sciences Touro College New York, New York

Elaine Roe, MD

Anna Sitkoff, BS, ND

Physician, Hall Health Center University of Washington Seattle, Washington

Herbalist Naturopathic Medicine Bastyr University Seattle, Washington

Sally J. Rockwell, PhD, CCN

Robert A. Ronzio, PhD Executive Director Research and Educational Services Insight Learning Institute Austin, Texas

Angela Sadlon, ND All Encompassing Healthcare Centralia, Washington

Lahnor Powell, ND, MPH

Alexander G. Schauss, PhD

Medical Education Specialist Department of Medical Affairs Genova Diagnostics Duluth, Georgia

Senior Director of Research Natural and Medicinal Products Research AIBMR Life Sciences, Inc. Seattle, Washington Research Associate Bio5 Institute University of Arizona Tucson, Arizona Research Associate Geosciences University of Arizona Tucson, Arizona

Matt Pratt-Hyatt, PhD Associate Lab Director The Great Plains Laboratory, Inc. Lenexa, Kansas

Barbara Siminovich-Blok, ND, LAc

Pamela Snider, ND Executive and Senior Editor Foundations of Naturopathic Medicine Project Foundations of Naturopathic Medicine Institute Snoqualmie, Washington Associate Professor College of Naturopathic Medicine National University of Natural Medicine Portland, Oregon Faculty School of Naturopathic Medicine Bastyr University Kenmore, Washington Co-Founder Integrative Health Policy Consortium Conifer, Washington

CONTRIBUTORS

Virender Sodhi, MD (Ayurveda), ND

Sherry Torkos, BSc, Phm, RPh

Vijayshree Yadav, MD, MCR, FAAN

Founder Ayurvedic Naturopathic Medical Clinic Bellevue, Washington Founder and Chief Executive Officer Ayush Herbs Redmond, Washington

Pharmacist and Author Fort Erie, Ontario, Canada

Associate Professor Neurology Oregon Health & Science University Portland, Oregon

Nick Soloway, LMT, DC, LAc Private Practice Helena, Montana

Jessica Tran, ND, MBA Private Practice Environmental Medicine Wellness Integrative Naturopathic Center, Inc. Irvine, California

Michael Traub, ND, DHANP, FABNO Lindsey Stuart, MS, CNM

Alumni Naturopathic Medicine National University of Natural Medicine Portland, Oregon

Medical Director Dermatology Lokahi Health Center Kailua Kona, Hawaii Clinical Professor of Graduate Medical Education Postgraduate Education Bastyr University Seattle, Washington

Mollie Parker Szybala, ND, MPH

Roy Upton, RH

Doctor Naturopathic Medicine Sun Valley Natural Medicine Ketchum, Idaho

President American Herbal Pharmacopoeia Scotts Valley, California

Certified Nurse Midwife Boulder, Colorado

Cory Szybala, ND

Venessa Wahler, ND Jade Teta, ND Owner/Founder/CEO Metabolic Effect Inc. Greensboro/Winston-Salem, North Carolina

Lead ND Naturopathic Medicine Tummy Temple Seattle, Washington

Keoni Teta, ND

Edward C. Wallace, ND, DC

Owner The Naturopathic Health Clinic of North Carolina Greensboro/Winston-Salem, North Carolina

Medical Education Specialist Medical Affairs Genova Diagnostics Asheville, North Carolina

Brice Thompson, ND, MS

Terry Willard, CIH, PhD

Postdoctoral Scholar Department of Pharmaceutics University of Washington Seattle, Washington

Founder Wild Rose College of Natural Healing Calgary, Canada

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Eric L. Yarnell, ND, RH(AHG) Professor Botanical Medicine Bastyr University Kenmore, Washington Chief Medical Officer Northwest Naturopathic Urology Seattle, Washington

Jared Zeff, ND Naturopathic Physician Salmon Creek Clinic Portland, Oregon

Heather Zwickey, PhD Professor School of Graduate Studies National University of Natural Medicine Portland, Oregon Adjunct Faculty Neurology Oregon Health and Science University Portland, Oregon Human Nutrition and Functional Medicine University of Western States Portland, Oregon

P R E FA C E This fifth edition of the Textbook of Natural Medicine (which has now been in publication since 1985) brings several new features and changes to our structure and format. We are especially excited that we are in full color for the first time, including images and figures. These dramatically improve our ability to present, in a more understandable and visually interesting way, the key concepts of and insights into the underlying causes of dysfunction and disease. We are also delighted that with all the new chapters and graphics, Elsevier has moved us back to the two-volume format. To better fit the content into two logical volumes, we changed the order (and some of the titles) of the sections. Syndromes and Special Topics moved to Section V because these fit better in Volume 2 with Section VI, Diseases. Pharmacology of Natural Medicines moved to Section IV because this fits better with Volume 1. As usual, we offer many new chapters, and we think the new chapter on sarcopenia is of particular importance. In addition to new chapters, some chapters have been renamed for better consistency, and some have been moved to sections that we felt were more appropriate. To

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facilitate utilization, the sections are now color coded, and we have provided alphabetical tabs to help readers in searching for specific diseases. Closely related diseases have been placed in a single chapter―for example, depression, dysthymia, manic phase, and seasonal affective disorder are all located in the chapter on affective disorders chapter―so becoming familiar with these groupings is essential for finding specific diseases. There are now 14 appendices that provide additional resources for the clinician. We worked with authors to make their writing more succinct and eliminate unnecessary content. We also reduced the length of Section VI by removing duplication of content from Section V in the therapeutics portion of the chapters. We hope you will be as pleased with the latest edition as we are. Due to the substantial increase in pages this edition, to keep down costs we had to move all of the approximately 20,000 references to the online version. Joseph E. Pizzorno Michael T. Murray

ACKNOWLED GMENTS We would like to thank Inta Ozols, the original commissioning editor, our executive assistant Lavelle Brown (who so effectively organized and managed all the authors and chapters), and the dedicated staff at Elsevier (Kristin Wilhelm, Linda Woodard, Laurie Gower, Becky Leenhouts, Jeff Patterson, Julie Eddy, Clay Broeker, Margaret Reid, Deanna Sorenson, and Allison Kieffer) for their excellent work in making this the best edition ever.

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SECTION

1

Philosophy of Natural ­Medicine One of the key features of the various schools of natural medicine that differentiates them from conventional medicine is their strong philosophical foundation. The basic philosophical premise of naturopathic medicine, for example, is that there is an inherent healing power in nature and in every human being. We believe that a primary role of the physician is to “remove the blocks to cure” and enhance this innate healing power within his or her patients. In many ways, this was the most difficult section of the textbook to write because, before this textbook, no comprehensive history of the social, political, and philosophical development of naturopathic medicine had ever been written. Even in the halcyon years of the 1920s and 1930s, the profession was never able to agree upon a concise philosophy. This situation has now changed. In this section, we provide well-documented chapters detailing the roots of American natural medicine. After a century of maturation, the naturopathic profession has now widely agreed to a comprehensive definition, set of principles, and system of case analysis that provide a systematic guide for the application of these concepts in a clinical setting. The seven fundamental principles of naturopathic medicine are as follows: The healing power of nature (vis medicatrix naturae) First, do no harm (primum non nocere) Find the cause (tolle causam) Treat the whole person Preventive medicine Wellness Doctor as teacher These principles translate into the following questions the practitioner applies when analyzing a case: • What is the first cause; what is contributing now? • How is the body trying to heal itself? • What is the minimum level of intervention needed to facilitate the self-healing process? • What are the patient’s underlying functional weaknesses? • What education does the patient need to understand why he or she is sick and how to become healthier? • How does the patient’s physical disease relate to his or her psychological and spiritual health? We have further expanded on the philosophical basis of naturopathic medicine by having these concepts addressed by several authors whose backgrounds allow each of them a unique and, we believe, complementary insight into some of the fundamental questions of the goals of health care. Although the dominant school of medicine has essentially ignored these issues, we believe that the true physician cannot function without a sound philosophical basis to guide his or her actions. Without more than a superficial understanding of health and disease, the physician is more likely to function as a technician, temporarily alleviating symptoms while allowing the real disease to progress past the point of recovery. The huge and increasing burden of chronic disease in all age groups clearly validates the predictions of the founders of naturopathic medicine that primarily treating symptoms, while not addressing causes, results in increased chronic disease.

1

1 Functional Medicine: A 21st-Century Model of Patient Care and Medical Education Robert Luby, MD, and Leo Galland*, AB, MD OUTLINE What Is Functional Medicine?, 2 Principles, 2 Lifestyle and Environmental Factors, 4 Fundamental Physiological Processes, 4 Core Clinical Imbalances, 4 Antecedents, Triggers, and Mediators, 5 Antecedents and the Origins of Illness, 5

Triggers and the Provocation of Illness, 5 Mediators and the Formation of Illness, 6 Constructing the Model, 6 Assessment, 6 The Functional Medicine Matrix Model, 6 The Healing Partnership, 8 Integration of Care, 10

In this chapter, the basic principles, constructs, and methodology of functional medicine are reviewed. It is not the purpose of this chapter to recapitulate the range and depth of the science underlying functional medicine; books and monographs covering that material in great detail are already available for the interested clinician and for use in health professional schools (see Bibliography at the end of the chapter). The purpose is to describe how functional medicine is organized to deliver personalized systems medicine and is equipped to respond to the challenge of treating complex chronic disease more effectively.

has not really produced an efficient method for identifying and assessing changes in basic physiological processes that produce symptoms of increasing duration, intensity, and frequency, although it is known that such alterations in function often represent the first signs of conditions that, at a later stage, become pathophysiologically definable diseases. By broadening the use of functional to encompass this view, functional medicine becomes the science and art of detecting and reversing alterations in function that clearly move a patient toward chronic disease over the course of a lifetime. One way to conceptualize where functional medicine falls in the continuum of health and health care is to examine the functional medicine “tree.” In its approach to complex chronic disease, functional medicine encompasses the whole domain represented by the graphic shown in Fig. 1.1, but it first addresses the patient’s core clinical imbalances (found in the functional physiological organizing systems); the fundamental lifestyle factors that contribute to chronic disease; and the antecedents, triggers, and mediators that initiate and maintain the disease state. Diagnosis, of course, is part of the functional medicine model, but the emphasis is on understanding and improving the functional core of the human being as the starting point for intervention. Functional medicine clinicians focus on restoring balance and improved function in the dysregulated systems by strengthening the fundamental physiological processes that underlie them and by adjusting the environmental and lifestyle inputs that nurture or impair them. This approach leads to therapies that focus on restoring health and function, rather than simply controlling signs and symptoms. 

WHAT IS FUNCTIONAL MEDICINE? Functional medicine encompasses a dynamic approach to assessing, preventing, and treating complex chronic disease. It helps clinicians of all disciplines identify and ameliorate dysfunctions in the physiology and biochemistry of the human body as a primary method of improving patient health. This model of practice emphasizes that chronic disease is almost always preceded by a period of declining function in one or more of the body’s physiological organizing systems. Returning patients to health requires reversing (or substantially improving) the specific dysfunctions that contributed to the disease state. Those dysfunctions are, for each of us, the result of lifelong interactions among diet, environment, lifestyle choices, and genetic predispositions. Each patient, therefore, represents a unique, complex, and interwoven set of influences on intrinsic functionality that, over time, set the stage for the development of disease or the maintenance of health. To manage the complexity inherent in this approach, functional medicine has adopted practical models for obtaining and evaluating clinical information that leads to individualized patient-centered therapies. Historically, the word functional was used somewhat pejoratively in medicine. It implied a disability associated with either a geriatric or psychiatric problem. The authors suggest, however, that this is a very limited definition of an extremely useful word. The medical profession

*Previous edition contributor

2

PRINCIPLES Seven basic principles characterize the functional medicine paradigm: • Acknowledging the biochemical individuality of each human being, based on the concepts of genetic and environmental uniqueness • Incorporating a patient-centered rather than a disease-centered approach to treatment

CHAPTER 1 

Functional Medicine: A 21st-Century Model of Patient Care and Medical Education

The Functional Medicine Tree

Cardiology

Pulmonary

Endocrinology

Urology

Organ System Diagnosis

Gastroenterology

Hepatology Neurology

Immunology

Signs and Symptoms

The Fundamental Organizing Systems and Core Clinical Imbalances Assimilation

Energy

Digestion, Absorption, Microbiota/Gl, Respiration

Energy regulation, Mitochondrial function

Cardiovascular, Lymphatic systems

Biotransformation and Elimination

Structural Integrity

Defence and Repair

Toxicity, Detoxification

From the subcellular membranes to the musculoskeletal system

Immune system, Inflammatory processes, Infection and microbiota

Transport

Communication

Endocrine, Neurotransmitters, Immune messengers, Cognition

Antecedents, Triggers, and Mediators Mental, Emotional, Spiritual Influences

Genetic Predisposition

Experiences, Attitudes, Beliefs

Relationships

Sleep & Relaxation Exercise & Movement

Stress Nutrition

Personalizing Lifestyle and Environmental Factors Version 2

© 2015 The Institute for Functional Medicine

Fig. 1.1  The continuum of health and health care: the functional medicine tree. (Courtesy the Institute for Functional Medicine.)

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• Seeking a dynamic balance among the internal and external factors in a patient’s body, mind, and spirit • Addressing the web-like interconnections of internal physiological factors • Identifying health as a positive vitality—not merely the absence of disease—and emphasizing those factors that encourage a vigorous physiology • Promoting organ, cellular, and subcellular function as the means of enhancing the health span, not just the life span, of each patient • Staying abreast of emerging research—a science- and evidence-based approach 

LIFESTYLE AND ENVIRONMENTAL FACTORS The building blocks of life, and the primary influences on them, are found at the base of the functional medicine tree graphic (see Fig. 1.1). When we talk about influencing gene expression, we are interested in the interaction between lifestyle and environment in the broadest sense and any genetic predispositions with which a person may have been born— in a word, the epigenome. (Epigenetics is the study of how environmental factors can affect gene expression without altering the actual DNA sequence and how these changes can be inherited through generations.) Many environmental factors that affect gene expression are (or appear to be) a matter of choice (such as diet and exercise), others are very difficult for the individual patient to alter or escape (air and water quality, toxic exposures), and still others may be the result of unavoidable accidents (trauma, exposure to harmful microorganisms). Some factors that may appear modifiable are heavily influenced by the patient’s economic status—if you are poor, for example, it may be impossible to choose more nutritious food, decrease stress in the workplace and at home, or take the time to exercise and rest properly. Existing health status is also a powerful influence on the patient’s ability to alter environmental input. If you have chronic pain, exercise may be extremely difficult; if you are depressed, self-activation is a major challenge. The influence of these lifestyle and environment factors on the human organism is indisputable,1,2 and they are often powerful agents in the attempt to restore health. Neglecting to address them in favor of merely writing a prescription—whether for pharmaceutical agents, nutraceuticals, or botanicals—means the cause of the underlying dysfunction may itself remain unaddressed and further able to contribute to the genesis of other disease conditions. In general terms, the following factors should be considered when working to reverse dysfunction or disease and restore health: • Diet (type, quality, and quantity of food; food preparation; calories, fats, proteins, carbohydrates) • Nutrients (both dietary and supplemental) • Air and water • Microorganisms (and the general condition of the soil in which food is grown) • Physical exercise • Trauma • Psychosocial and spiritual factors, such as meaning and purpose, relationships, work, community, economic status, stress, and belief systems • Xenobiotics • Radiation 

FUNDAMENTAL PHYSIOLOGICAL PROCESSES There are certain physiological processes that are necessary to life. These are the “upstream” processes that can go awry and create “downstream” dysfunctions that eventually become expressed as

disease entities. Functional medicine requires that clinicians consider these in evaluating patients so that interventions can target the most fundamental level possible. These processes are as follows: 1. Communication • Intracellular • Intercellular • Extracellular 2. Bioenergetics/energy transformation 3. Assimilation 4. Structural integrity 5. Biotransformation/elimination 6. Defense and repair 7. Transport/circulation These fundamental physiological processes are usually taught early in health professions curricula, where they are appropriately presented as the foundation of modern, scientific patient care. Unfortunately, subsequent training in the clinical sciences often fails to fully integrate knowledge of the functional mechanisms of disease with therapeutics and prevention, emphasizing organ system diagnosis instead.3 Focusing predominantly on organ-system diagnosis without examining the underlying physiology that produced the patient’s signs, symptoms, and disease often leads to managing patient care by matching diagnosis to pharmacology. The job of the health care provider then becomes a technical exercise in finding the drug or procedure that best fits the diagnosis (not necessarily the patient or the underlying physiological dysfunction), leading to a significant curtailment of critical thinking pathways: “Medicine, it seems, has little regard for a complete description of how myriad pathways result in any clinical state.”4 Even more important, pharmacological treatments (and even natural remedies) are often prescribed without careful consideration of their physiological effects across all organ systems, physiological processes, and genetic variations.5 This was notably exemplified by the cyclooxygenase-2 inhibitor drugs that were so wildly successful on their introduction, only to be subsequently withdrawn or substantially narrowed in use because of collateral damage.6,7 

CORE CLINICAL IMBALANCES The functional medicine approach to assessment, both before and after diagnosis, charts a course using different navigational assumptions. Every health condition instigates a quest for information centered on understanding when and how the specific biological system(s) under examination became dysregulated and began manifesting dysfunction and/or disease. Analyzing all the elements of the patient’s story, the signs and symptoms, and the laboratory assessment through a matrix focused on functionality requires analytical thinking and a willingness on the part of the clinician to reflect deeply on the underlying biochemistry and physiology. The foundational principles of how the human organism functions—and how its systems communicate and interact—are essential to the process of linking ideas about multifactorial causation with the perceptible effects called disease or dysfunction. To assist clinicians in this process, functional medicine identified and organized a set of core clinical imbalances that are linked to the fundamental physiological processes (organizing systems). These serve to marry the mechanisms of disease with the manifestations and diagnoses of disease. Many common underlying pathways of disease are reflected in these clinical imbalances. The following list of imbalanced systems and processes is not definitive, but some of the most common examples are provided. We recommend that the organizing systems be considered in the order as shown in the following list: • Digestion • Absorption

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5

One Condition – Many Imbalances Inflammation

Endocrine

Genetics and epigenetics

Diet and exercise

Mood disorders

OBESITY One Imbalance – Many Conditions INFLAMMATION

Heart disease Depression Arthritis Cancer Diabetes Fig. 1.2  Core clinical imbalances—multiple influences. (Courtesy the Institute for Functional Medicine.)

• Microbiome/gastrointestinal • Respiration • Immune system • Inflammatory processes • Infection and microbiome • Energy regulation • Mitochondrial function • Toxicity • Detoxification • Endocrine • Neurotransmitter • Immune messengers • Cognition • From the subcellular membranes • To the musculoskeletal system Using this construct, it becomes much clearer that one disease and/ or condition may have multiple causes (i.e., multiple clinical imbalances), just as one fundamental imbalance may be at the root of many seemingly disparate conditions (Fig. 1.2). The most important precept to remember about functional medicine is that restoring balance—in the patient’s lifestyle and/or environment and in the body’s fundamental physiological processes—is the key to restoring health. 

to acute or chronic illness. For a person who is ill, antecedents form the illness diathesis. From the perspective of prevention, they are risk factors. Knowledge of antecedents provides a rational structure for the organization of preventive medicine and public health. Medical genomics seeks to better understand disease by identifying the phenotypic expression of disease-related genes and their products. The application of genomic science to clinical medicine requires the integration of antecedents (genes and the factors controlling their expression) with mediators (the downstream products of gene activation). Mediators, triggers, and antecedents are not only key biomedical concepts; they are also important psychosocial concepts. In person-centered diagnosis, the mediators, triggers, and antecedents for each person’s illness form the focus of the clinical investigation.

Antecedents and the Origins of Illness Understanding the antecedents of illness helps the physician understand the unique characteristics of each patient as they relate to his or her current health status. Antecedents may be thought of as congenital or developmental. The most important congenital factor is gender: women and men differ sharply in susceptibility to many disorders. The most important developmental factor is age; what ails children is rarely the same as what ails the elderly. Beyond these obvious factors lies a diversity as complex as the genetic differences and separate life experiences that distinguish one person from another. 

ANTECEDENTS, TRIGGERS, AND MEDIATORS8

Triggers and the Provocation of Illness

What modern science has taught us about the genesis of disease can be represented by three words: triggers, mediators, and antecedents. Triggers are discrete entities or events that provoke disease or its symptoms. Microbes are an example. The greatest scientific discovery of the 19th century was the microbial etiology of the major epidemic diseases. Triggers are usually insufficient in and of themselves for disease formation; however, host response is an essential component. It is, therefore, the functional medicine practitioner’s job to know not just the patient’s ailments or diagnoses but also the physical and social environment in which illness occurs, the dietary habits of the person (present diet and preillness diet), his or her beliefs about the illness, the effect of illness on social and psychological function, factors that aggravate or ameliorate symptoms, and factors that predispose to illness or facilitate recovery. This information is necessary for establishing a functional medicine treatment plan. Identifying the biochemical mediators that underlie host responses was the most productive field of biomedical research during the second half of the 20th century. Mediators, as the word implies, do not cause disease. They are intermediaries that contribute to the manifestation and/or continuation of disease. Antecedents are factors that predispose

A trigger is anything that initiates an acute illness or the emergence of symptoms. The distinction between a trigger and a precipitating event is relative, not absolute; the distinction helps organize the patient’s story. As a general rule, triggers only provoke illness as long as the person is exposed to them (or for a short while afterward), whereas a precipitating event initiates a change in health status that persists long after the exposure ends. Common triggers include physical or psychic trauma, microbes, drugs, allergens, foods (or even the act of eating or drinking), environmental toxins, temperature change, stressful life events, adverse social interactions, and powerful memories. For some conditions, the trigger is such an essential part of our concept of the disease that the two cannot be separated; the disease is either named after the trigger (e.g., strep throat) or the absence of the trigger negates the diagnosis (e.g., concussion cannot occur without head trauma). For chronic ailments like asthma, arthritis, or migraine headaches, multiple interacting triggers may be present. All triggers, however, exert their effects through the activation of host-derived mediators. In closed-head trauma, for example, activation of N-methyl-d-aspartic acid receptors, induction of nitric oxide synthase, and liberation of free intraneuronal calcium

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BOX 1.1  Common Illness Mediators Biochemical Hormones Neurotransmitters Neuropeptides Cytokines Free radicals Transcription factors  Subatomic Ions Electrons Electrical and magnetic fields  Cognitive/Emotional Fear of pain or loss Feelings or personal beliefs about illness Poor self-esteem, low perceived self-efficacy Learned helplessness Lack of relevant health information  Social/Cultural Reinforcement for staying sick Behavioral conditioning Lack of resources because of social isolation or poverty The nature of the sick role and the doctor–patient relationship

determine the late effects. Intravenous magnesium at the time of trauma attenuates the severity by altering the mediator response.9,10 Sensitivity to different triggers often varies among persons with similar ailments. A prime task of the functional practitioner is to help patients identify important triggers for their ailments and develop strategies for eliminating them or diminishing their virulence. 

Mediators and the Formation of Illness A mediator is anything that produces or perpetuates symptoms or damages tissues of the body, including certain behaviors. Mediators vary in form and substance. They may be biochemical (e.g., prostanoids and cytokines), ionic (e.g., hydrogen ions), social (e.g., reinforcement for staying ill), psychological (e.g., fear), or cultural (e.g., beliefs about the nature of illness). A list of common mediators is presented in Box 1.1. Illness in any single person usually involves multiple interacting mediators. Biochemical, psychosocial, and cultural mediators interact continuously in the formation of illness. 

CONSTRUCTING THE MODEL Assessment Combining the principles, lifestyle and environment factors, fundamental physiological processes, antecedents, triggers, mediators, and core clinical imbalances demands a new architecture for gathering and sorting information for clinical practice—in effect, a new heuristic to serve the practice of functional medicine. (Heuristics are rules of thumb—ways of thinking or acting—that develop through experimentation and enable more efficient and effective processing of data.) This new model includes an explicit emphasis on principles and mechanisms that infuse meaning into the diagnosis and deepen the clinician’s understanding of the multivalent contributors to physiological dysfunction. Any methodology for constructing a coherent story and an effective therapeutic plan in the context of complex chronic illness must be flexible and adaptive. Like an accordion file that compresses

and expands upon demand, the amount and kind of data collected will necessarily change in accordance with the patient’s situation and the clinician’s time and ability to piece together the underlying threads of dysfunction. The conventional assessment process involving the chief complaint, history of present illness, and past medical history sections must be expanded (Fig. 1.3) to include a thorough investigation of antecedents, triggers, and mediators and a systematic evaluation of any imbalances within the fundamental organizing systems. Personalized medical care without this expanded investigation falls short. 

The Functional Medicine Matrix Model Distilling the data from the expanded history, physical examination, and laboratory findings into a narrative storyline that includes antecedents, triggers, and mediators can be challenging. Key to developing a thorough narrative is organizing the story using the Functional Medicine Matrix Model form (Fig. 1.4). The matrix form helps organize and prioritize information and also clarifies the level of present understanding, thus illuminating where further investigation is needed. For example: • Indicators of inflammation on the matrix might lead the clinician to request tests for specific inflammatory markers (such as highly sensitive C-reactive protein, interleukin levels, and/or homocysteine). • Essential fatty acid levels, methylation pathway abnormalities, and organic acid metabolites help determine the adequacy of dietary and nutrient intakes. • Markers of detoxification (glucuronidation and sulfation, cytochrome P450 enzyme heterogeneity) can determine the functional capacity for molecular biotransformation. • Neurotransmitters and their metabolites (vanilmandelate, homovanillate, 5-hydroxyindoleacetate, quinolinate) and hormone cascades (gonadal and adrenal) have obvious utility in exploring messenger molecule balance. • Computed tomographic scans, magnetic resonance imaging (MRI), or plain radiographs extend the view of the patient’s structural dysfunctions. The use of bone scans, dual-energy x-ray absorptiometry scans, or bone resorption markers11,12 can be useful in further exploring the web-like interactions of the matrix. • Newer, useful technologies such as functional MRIs, single-photon emission computed tomography, and positron emission tomographic scans offer a more comprehensive assessment of metabolic function within organ systems. It is the process of completing a comprehensive history and physical using the expanded functional medicine heuristic and then charting these findings on the matrix that best directs the choice of diagnostic evaluations and successful treatment. Therapies should be chosen for their potential effect on the most significant imbalances of the particular patient. A completed matrix form facilitates review of common pathways, mechanisms, and mediators of disease and helps clinicians select points of leverage for treatment strategies. However, even with the matrix as an aid to synthesizing and prioritizing information, it can be very useful to consider the effect of each variable at five different levels: 1. Whole-body interventions: Because the human organism is a complex adaptive system, with countless points of access, interventions at one level will affect points of activity in other areas as well. For example, improving the patient’s sleep beneficially influences the immune response, melatonin levels, and T-cell lymphocyte levels and helps decrease oxidative stress. Exercise reduces stress, improves insulin sensitivity, and improves detoxification. Reducing stress (and/or improving stress management) reduces cortisol

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7

Chief Complaint (CC) History of Present Illness (HPI) Past Medical History (PMH) – Explore antecedents, triggers, and mediators of CC, HPI, and PMH Family Medical History – Genetic predispositions? Review of Organ Systems (ROS) Medication and Supplement History Dietary History Social, Lifestyle, Exercise History Physical Examination (PE) Laboratory and Imaging Evaluations Explore Core Clinical Imbalances: Assimilation Imbalances Digestion Absorption Microbiota/GI Respiration Defense and Repair Imbalances Immune system Inflammatory processes Infection and microbiota Energy Imbalances Energy regulation Mitochondrial function Biotransformation and Elimination Imbalances Toxicity Detoxification Communication Imbalances Endocrine Neurotransmitter Immune messengers Cognition Structural Integrity Imbalances From the subcellular membranes to the musculoskeletal system Initial Assessment: – Enter data on Matrix form; look for common themes – Review underlying mechanisms of disease – Recapitulate patient’s story – Organ system-based diagnosis – Functional medicine assessment: underlying mechanisms of disease; genetic and environmental influences Treatment Plan: – Individualized – Dietary, lifestyle, environmental – Nutritional, botanical, psychosocial, energetic, spiritual – May include pharmaceuticals and/or procedures Fig. 1.3  Expanding the accordion file: the functional medicine assessment heuristic. (Courtesy the Institute for Functional Medicine.)

levels, improves sleep, improves emotional well-being, and reduces the risk of heart disease. Changing the diet has myriad effects on health, from reducing inflammation to reversing coronary artery disease. 2. Organ-system interventions: These interventions are used more frequently in the acute presentation of illness. Examples include splinting; draining lesions; repairing lacerations; reducing fractures, pneumothoraxes, hernias, or obstructions; or removing a stone to reestablish whole-organ function. There are many interventions that improve organ function. For example, bronchodilators improve air exchange, thereby decreasing hypoxia, reducing oxidative stress, and improving metabolic function and oxygenation in a patient with reactive airway disease. 3. Metabolic or cellular interventions: Cellular health can be addressed by ensuring the adequacy of macronutrients, essential amino acids,

vitamins, and cofactor minerals in the diet (or, if necessary, from supplementation). An individual’s metabolic enzyme polymorphisms can profoundly affect his or her nutrient requirements. For example, adding conjugated linoleic acid to the diet can alter the peroxisome proliferator–activated receptor system, affect body weight, and modulate the inflammatory response.13–15 However, in a person who is diabetic or insulin resistant, adding conjugated linoleic acid may induce hyperproinsulinemia, which is detrimental.16,17 Altering the types and proportions of carbohydrates in the diet may increase insulin sensitivity, reduce insulin secretion, and fundamentally alter metabolism in the insulin-resistant patient. Supporting liver detoxification pathways with supplemental glycine and N-acetylcysteine improves the endogenous production of adequate glutathione, an essential antioxidant in the central nervous system and gastrointestinal tract.

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FUNCTIONAL MEDICINE MATRIX Retelling the Patient’s Story Antecedents (Predisposing Factors— Genetic/Environmental)

Triggering Events (Activators)

Physiology and Function: Organizing the Patient’s Clinical Imbalances Assimilation

Defense & Repair (e.g., Immune, Inflammation, Infection/Microbiota)

(e.g., Digestion, Absorption, Microbiota/GI, Respiration)

Structural Integrity (e.g., from Subcellular Membranes to Musculoskeletal Structure)

Mental

Emotional

e.g., cognitive function, perceptual patterns

e.g., emotional regulation, grief, sadness, anger, etc.

Energy (e.g., Energy Regulation, Mitochondrial Function)

Spiritual Mediators/Perpetuators (Contributors)

e.g., meaning & purpose, relationship with something greater

Communication (e.g., Endocrine, Neurotransmitters, Immune messengers)

Biotransformation & Elimination (e.g., Toxicity, Detoxification)

Transport (e.g., Cardiovascular, Lymphatic System)

Modifiable Personal Lifestyle Factors Sleep & Relaxation

Name:

Exercise & Movement

Nutrition

Date:

Stress

CC:

Relationships

© 2015 Institute for Functional Medicine Version3

Fig. 1.4  The Functional Medicine Matrix Model. (Courtesy the Institute for Functional Medicine.)

4. Subcellular/mitochondrial interventions: There are many examples of nutrients that support mitochondrial function.18,19 Inadequate iron intake causes oxidants to leak from mitochondria, damaging mitochondrial function and mitochondrial DNA. Making sure there is sufficient iron helps alleviate this problem. Inadequate zinc intake (found in more than 10% of the U.S. population) causes oxidation and DNA damage in human cells.19 Ensuring the adequacy of antioxidants and cofactors for the at-risk individual must be considered in each part of the matrix. Carnitine, for example, is required as a carrier for the transport of fatty acids from the cytosol into the mitochondria, improving the efficiency of β-oxidation of fatty acids and resultant adenosine triphosphate production. In patients who have lost significant weight, carnitine undernutrition can result in fatty acids undergoing ωoxidation, a far less efficient form of metabolism.20 Patients with low carnitine may also respond to riboflavin supplementation.20 5.  Subcellular/gene-expression interventions: Many compounds interact at the gene level to alter cellular response, thereby affecting health and healing. Any intervention that alters nuclear factor-κB entering the nucleus, binding to DNA, and activating genes that encode inflammatory modulators, such as interleukin-6 (and thus C-reactive protein), cyclooxygenase-2, interleukin-1, lipoxygenase, inducible nitric oxide synthase, tumor necrosis factor-α, or a number of adhesion molecules, will affect many disease conditions.21,22 There are many ways to alter the environmental triggers for nuclear factor-κB, including lowering oxidative stress; altering emotional stress; and consuming adequate phytonutrients, antioxidants, alpha-lipoic acid, eicosapentaenoic acid, docosahexaenoic acid,

and γ-linoleic acid.21 Adequate vitamin A allows the appropriate interaction of vitamin A–retinoic acid with more than 370 genes.23 Vitamin D in its most active form intercalates with a retinol protein and the DNA exon and modulates many aspects of metabolism, including cell division in both healthy and cancerous breast, colon, prostate, and skin tissue.24 Vitamin D has key roles in controlling inflammation, calcium homeostasis, bone metabolism, cardiovascular and endocrine physiology, and healing.24 Experience using this model, along with improved pattern-recognition skills, will often lessen the need for extensive laboratory assessments. However, there will always be certain clinical conundrums that simply cannot be assessed without objective data, and for most patients, there may be an irreducible minimum of laboratory assessments required to accumulate information. For example, in the clinical workup of autism spectrum disorders in children, heavy-metal exposure and toxicity may play an important role. The heavy-metal body burden cannot be sensibly assessed without laboratory studies. In most initial workups, laboratory and imaging technologies can be reserved for those complex cases in which the initial interventions prove insufficient to the task of functional explication. When clinical acumen and educated steps in both assessments and therapeutic trials do not yield expected improvement, laboratory testing often provides rewarding information. This is frequently the context for focused genomic testing. 

The Healing Partnership No discussion of the functional medicine model would be complete without mention of the therapeutic relationship. Partnerships are

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Functional Medicine: A 21st-Century Model of Patient Care and Medical Education

formed to achieve an objective. For example, a business partnership forms to engage in commercial transactions for financial gain; a marriage partnership forms to build a caring, supportive, home-centered environment. A healing partnership forms to heal the patient through the integrated application of both the art of medicine (insight driven) and the science of medicine (evidence driven). An effective partnership requires that trust and rapport be established. Patients must feel comfortable telling their stories and revealing intimate information and significant events. In the 20th century, contemporary medicine, traditionally considered a healing profession, evolved away from the role of healing the sick to that of curing disease through modern science. Research into this transition revealed that healing was traditionally associated with themes of wholeness, narrative, and spirituality. Professionals and patients alike report healing as an intensely personal, subjective experience involving a reconciliation of meaning for an individual and a perception of wholeness. The biomedical model as currently configured no longer encompasses these characteristics. Contemporary medicine considers the wholeness of healing to be beyond its orthodoxy—the domain of the nonscientific and nonmedical.25 We disagree. To grasp the profound importance of the healing partnership to the creation of a system of medicine adequate to the demands of the 21st century, an emerging body of relevant research was reviewed.26–28 As Louise Acheson, MD, MS, associate editor of the Annals of Family Practice, articulated insightfully in that journal29: “It is challenging to research this ineffable process called healing.” Hsu and colleagues asked focus groups of nurses, physicians, medical assistants, and randomly selected patients to define healing and describe what facilitates or impedes it.30 The groups arrived at surprisingly convergent definitions: “Healing is a dynamic process of recovering from a trauma or illness by working toward realistic goals, restoring function, and regaining a personal sense of balance and peace.” They heard from diverse participants that “healing is a journey” and “relationships are essential to healing.” Research into the role of healing in the medical environment has generated some thoughtful and robust investigations. Scott et  al.’s26 research into the healing relationship found very similar descriptions to those of Hsu et  al.30 The participants in the study27 articulated aspects of the healing partnership as follows: 1. Valuing and creating a nonjudgmental emotional bond 2. Appreciating power and consciously managing clinician power in ways that would most benefit the patient 3. Abiding and displaying a commitment to caring for patients over time Three relational outcomes result from these processes: trust, hope, and a sense of being known. Clinician competencies that facilitate these processes are self-confidence, emotional self-management, mindfulness, and knowledge.27 In this rich soil, the healing partnership flourishes. The characteristics of a conventional therapeutic encounter are fundamentally different from a healing partnership, and each emerges from specific emphases in training. In the therapeutic encounter, the relationship forms to assess and treat a medical problem using (usually) an organ-system structure, a differential diagnosis process, and a treatment toolbox focused on pharmacology and medical procedures. The therapeutic encounter pares down the information flow between physician and patient to the minimum needed to identify the organ-system domain of most probable dysfunction, followed by a sorting system search (the differential diagnosis heuristic). The purpose of this relationship is to arrive at the most probable diagnosis as quickly as possible and select an intervention based on probable efficacy. The relationship is a left-brain–guided conversation controlled

9

by the clinician and characterized by algorithmic processing and statistical thinking.31,32 The functional medicine healing partnership forms with a related but broader purpose: to help the patient heal by identifying the underlying mechanisms and influences that initiated and continue to mediate the patient’s illness(es). This type of relationship emphasizes shared responsibility for identifying the causes of the patient’s condition and achieving insight about enduring solutions. The healing partnership is critical to the delivery of personalized systems of medicine and to managing the uncertainty (choices under risk) inherent in clinical practice. In the healing partnership, the appropriate utilization and integration of left-brain and right-brain functions are found. In language, we have the fullest expression of the integration of leftand right-brain function. Language is so complex that the brain has to process it in different ways simultaneously—both denotatively and connotatively. For complexity and nuance to emerge in language, the left brain needs to see the trees, and the right brain helps us see and understand the forest.33,34 The starting point for creating a healing partnership is the patient’s experience. People, not diseases, can heal. Mindful integration of brain function is at the heart of a healing partnership. Some of the basic steps for establishing a healing partnership include the following: 1. Allowing patients to express, without interruption, their story about why they have come to see you. (Research focused on the therapeutic encounter has repeatedly found that clinicians interrupt the patient’s flow of conversation within the first 18 seconds or less, often denying the patient an opportunity to finish.35) The manner in which the patient frames the initial concerns often presages later insight into the root causes. Any interruption in this early stage of narrative moves the patient back into left-brain processing and away from insight.36 2. After focusing on the chief concerns, encouraging the patient’s narrative regarding the present illness(es). Clarifications can be elicited by further open-ended questioning (e.g., “Tell me more about that”; “What else do you think might be going on?”). During this portion of the interview, there is a switching back and forth between right- and left-brain functions. • During this conversation, signs and symptoms of the present illness are distributed by the practitioner into the Functional Medicine Matrix Model form as previously described. • Analysis of the data thus collected proceeds by assessing probable underlying causes—based on evidence about common underlying mechanisms of disease—and ongoing mediators of the disease. 3.  Next, conveying to the patient in the simplest terms possible that to achieve lasting solutions to the problem(s) for which the patient has come seeking help, a few fundamental questions must be asked and answered to understand the problem in the context of the patient’s personal life. This framing of the interview process moves the endeavor from a left-brain compilation to a narrative that encourages insight—based on complex pattern recognition— about the root causes of the problem. 4. At this stage, control is shared with the patient: “Without your help, we cannot understand your medical problem in the depth and breadth you deserve.” Implementing this shared investigation can be facilitated by certain approaches:

a.  For determining antecedent conditions, the following questions are useful: • When was the last time you felt well? When were you free of this problem? • What were the circumstances surrounding the appearance of the problem? • Have similar problems appeared in family members?

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One Condition, Many Causes

One Cause, Many Conditions

Omega-3 Deficiency

Depression

Antibiotic Use

Low Thyroid

Heart Disease

Arthritis

DEPRESSION

Pre-Diabetes

INFLAMMATION

Vitamin D Deficiency

Diabetes

Cancer

Cause

Condition

Fig. 1.5  Overview of the functional medicine (FM) model. (Courtesy the Institute for Functional Medicine.)

b. For triggers, the following question is critical: • What conditions, activities, or events seemed to initiate the problem? (Microbes and stressful personal events are examples but illustrate quite different categories of triggers. Triggers by themselves are usually insufficient for disease formation, so triggers must be viewed within the context of the antecedent conditions.) c. Mediators of the problem are influences that help perpetuate it. • There can be specific mediators of diseases in the patient’s activities, lifestyle, and environment. Many diverse factors can affect the host’s response to stressors. • Any of the core clinical imbalances, discussed previously and shown on the Functional Medicine Matrix Model, can transform what might have been a temporary change in homeostasis into a chronic allostatic condition. It helps at this juncture to emphasize again that the following issues are elemental in forming a healing partnership: • Only the patient can inform the partnership about the conditions that provided the soil from which the problem(s) under examination emerged. The patient literally owns the keys to the joint deliberation that can provide insight into the process of achieving a healing outcome. • The professional brings experience, wisdom, tools, and techniques and works to create the context for a healing insight to emerge. • The patient’s information, input, mindful pursuit of insight, and engagement become “the horse before the cart.” The cart carries the clinician—the person who guides the journey using evidence, experience, and judgment and who contributes the potential for expert insight.

The crux of the healing partnership is an equal investment of focus by both clinician and patient. They work together to identify the right places to apply leverage for change. Patients must commit to engage both their left-brain skills and their right-brain function to inform and guide the exploration to the next steps in assessment, therapy, understanding, and insight. Clinicians must also engage both the left-brain computational skills and the right-brain pattern-recognition functions that, when used together, can generate insight about the patient’s story. An overview of the functional medicine model is given in Fig. 1.5. 

INTEGRATION OF CARE Functional medicine explicitly recognizes that no single profession can cover all the viable therapeutic options. Interventions and practitioners will differ by training, licensure, specialty focus, and even by beliefs and ethnic heritage. However, all health care disciplines (and all medical specialties) can—to the degree allowed by their training and licensure and assuming a good background in Western medical science—use a functional medicine approach, including integrating the matrix as a basic template for organizing and coupling knowledge and data. Consequently, functional medicine can provide a common language, a flexible architecture, and a unified model to facilitate integrated and integrative care. Regardless of the discipline in which the clinician has been trained, developing a network of capable, collaborative practitioners with whom to comanage challenging patients and to whom referrals can be made for therapies outside the primary clinician’s own expertise will enrich patient care and strengthen the clinician–patient relationship.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Goetzel RZ. Do prevention or treatment services save money? The wrong debate. Health Aff. 2009;28(1):37–41. 2. Probst-Hensch NM. Chronic age-related diseases share risk factors: do they share pathophysiological mechanisms and why does that matter? Swiss Med Wkly. 2010;140:w13072. Available at http://www.smw.ch/ index.php?id=smw-2010-13072. Accessed October 11, 2010. 3. Magid CS. Developing tolerance for ambiguity. JAMA. 2001;285(1):88. 4. Rees J. Complex disease and the new clinical sciences. Science. 2002;296: 698–701. 5. Radford T. Top scientist warns of “sickness” in US health system. BMJ. 2003;326:416. https://doi.org/10.1136/bmj.326.7386.416/b. 6. Vioxx. Lessons for Health Canada and the FDA. CMAJ. 2005;172(11):5. 7. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021–2029. 8. This section was excerpted and adapted from Galland L. Patient-centered care: antecedents triggers, and mediators. In: Textbook of Functional Medicine, Ch. 8. 9. Cernak I, Savic VJ, Kotur J, et al. Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. J Neurotrauma. 2000;17(1):53–68. 10. Vink R, Nimmo AJ, Cernak I. An overview of new and novel pharmacotherapies for use in traumatic brain injury. Clin Exp Pharmacol Physiol. 2001;28(11):919–921. 11. Yu SL, Ho LM, Lim BC, Sim ML. Urinary deoxypyridinoline is a useful biochemical bone marker for the management of postmenopausal osteoporosis. Ann Acad Med Singapore. 1998;27(4):527–529. 12. Palomba S, Orio F, Colao A, et al. Effect of estrogen replacement plus low-dose alendronate treatment on bone density in surgically postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 1002;87(4): 1502–1508. 13. Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, et al. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARa. J Lipid Res. 1999;40:1426–1433. 14. Gaullier JM, Halse J, Hoye K, et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr. 2004;79:1118–1125. 15. O’Shea M, Bassaganya-Riera J, Mohede IC. Immunomodulatory ­properties of conjugated linoleic acid. Am J Clin Nutr. 2004;79(S): 1199S–1206S. 16. Malloney F, Yeow TP, Mullen A, et al. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 DM. Am J Clin Nutr. 2004;80(4):887–895. 17. Riserus U, Vessby B, Arner P, Zethelius B. Supplementation with CLA induces hyperproinsulinaemia in obese men: close association with impaired insulin sensitivity. Diabetalogia. 2004;47(6):1016–1019. 18. Ames BN. The metabolic tune-up: metabolic harmony and disease prevention. J Nutr. 2003;133:1544S–1548S. 19. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616–658. 20. Bralley JA, Lord RS. Laboratory Evaluations in Molecular Medicine: Nutrients, Toxicants and Metabolic Controls. Atlanta: Institute for Advances in Molecular Medicine; 2001. 21. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NFkB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107(2):135–142.

22. Tak PP, Firestein GS. NF-kB: a key role in inflammatory disease. J Clin Invest. 2001;107(1):7–11. 23. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43:1773–1808. 24. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular diseases. Am J Clin Nutr. 2004;80(suppl 6). 1678S–1688S. 25. Egnew TR. The meaning of healing: transcending suffering. Ann Fam Med. 2005;3(3):255–262. 26. Scott JG, Cohen D, DiCicco-Bloom B, et al. Understanding healing relationships in primary care. Ann Fam Med. 2008;6(4):315–322. 27. Miller WL, Crabtree BF, Duffy MB, et al. Research guidelines for assessing the impact of healing relationships in clinical medicine. Altern Ther Health Med. 2003;9(suppl 3):A80–A95. 28. Jackson C. Healing ourselves, healing others? first in a series. Holist Nurs Pract. 2004;18(2):67–81. 29. Acheson L. Community care, healing, and excellence in research. Ann Fam Med. 2008;6:290–291. 30. Hsu C, Phillips WR, Sherman KJ, et al. Healing in primary care: a vision shared by patients, physicians, nurses, and clinical staff. Ann Fam Med. 2008;6(4):307–314. 31. Brown M, Brown G, Sharma S. Evidence-Based to Value-Based Medicine. Chicago, IL: AMA Press; 2005. 32. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes RB. Evidence-Based Medicine: How to Practice and Teach EBM (3rd ed.). New York: Churchill Livingstone. 33. Fiore S, Schooler J. Right hemisphere contributions to creative problem solving: converging evidence for divergent thinking. In: Beeman M, Chiarello C, eds. Right hemisphere language comprehension: perspectives from cognitive neuroscience. Philadelphia, PA: Erlbaum Publishing; 1998:255– 284. 34. Seger CA, Desmond JE, Glover GH, et al. fMRI evidence for right hemisphere involvement in processing unusual semantic relationships. Neuropsychology. 2000;14:361–369. 35. Beckman DB, et al. The effect of physician behavior on the collection of data. Ann Intern Med. 1984;101:692–696. 36. Lehrer J. The annals of science: the eureka hunt. The New Yorker. 2008:s40–s45.

BIBLIOGRAPHY Galland L, Lafferty H. Gastrointestinal Dysregulation: Connections to Chronic Disease. (Functional Medicine Monograph). Gig Harbor, WA: The Institute for Functional Medicine; 2008. Hedaya R, Quinn S. Depression: advancing the paradigm (Functional Medicine Monograph). Gig Harbor, WA: The Institute for Functional Medicine. In: Jones DS, ed. Textbook of functional medicine. Gig Harbor, WA: The Institute for Functional Medicine; 2008. Jones DS, Hofmann L, Quinn S. 21st Century Medicine: a New Model for Medical Education and Practice (White Paper). Gig Harbor, WA: The Institute for Functional Medicine; 2009. Lukaczer D, Jones DS, Lerman RH, et al. Clinical Nutrition: A Functional Approach. 2nd ed. Gig Harbor, WA: The Institute for Functional Medicine; 2004. Vasquez A. Musculoskeletal Pain: Expanded Clinical Strategies (Functional Medicine Monograph). Gig Harbor, WA: The Institute for Functional Medicine; 2008.

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2 A Hierarchy of Healing: The Therapeutic Order

A Unifying Theory of Naturopathic Medicine Stephen P. Myers, ND, BMed PhD, Pamela Snider, ND, Jared Zeff, ND, and Zora DeGrandpre*, MS, ND

OUTLINE A Brief History of Naturopathic Medicine, 11 Original Philosophy and Theory, 12 Modern Naturopathic Clinical Theory: the Process of Development, 13 A Theory of Naturopathic Medicine, 15 Illness and Healing as Process, 16 The Naturopathic Model in Acute Illness, 16 The Naturopathic Model in Chronic Illness, 17 The Determinants of Health, 18 Therapeutic Order and Naturopathic Assessment, 18 The Assessment Order: Components of a Vitalistic Assessment of Illness, Healing, and Health, 18

Therapeutic Order, 20 Acute and Chronic Concerns, 21 Establish the Conditions for Health, 21 Stimulate the Self-Healing Mechanisms, 22 Support Weakened or Damaged Systems or Organs, 23 Address Structural Integrity, 23 Address Pathology: Use Specific Natural Substances, Modalities, or Interventions, 23 Address Pathology: Use Specific Pharmacological or Synthetic Substances, 24 Suppress Pathology, 24 Theory in Naturopathic Medicine, 24

A BRIEF HISTORY OF NATUROPATHIC MEDICINE1

The profession went through a period of decline, marked with internal disunity and paralleled by the rise of biomedicine and the promise of wonder drugs. By 1957, there was only one naturopathic college left. By 1975, only eight states still licensed naturopathic physicians, and by 1979, there were only six. A survey conducted in 1980 revealed that there were only about 175 naturopathic practitioners still licensed and practicing in the United States and Canada.6 In contrast, in 1951, the number was approximately 3000.7 The decline of naturopathic medicine after a rapid rise was due to several factors. By the 1930s, a significant tension developed within the profession regarding clinical naturopathic practice based on traditional principles; the development of unified standards; and the role of experimental, reductionist science as an element of professional development.8,9 Many naturopathic doctors questioned the capacity for the reductionist scientific paradigm to research naturopathic medicine objectively in its full scope.8,10,11 This tension split the profession of naturopathic physicians from within after the death of Lust in the late 1940s, at a time when the profession was subject to both significant external forces and internal leadership challenges. This perception created a mistrust of science and research. Science was also frequently used as a bludgeon against naturopathic medicine, and the biases inherent in what became the dominant paradigm of scientific reductionism made a culture of scientific progress in the profession challenging. The discovery of effective antibiotics elevated the standard medical profession to dominant and unquestioned ­stature by

In 1900 Benedict Lust “invented” naturopathy, as an eclectic practice that combined many natural therapies and therapeutic systems under the umbrella of a comprehensive philosophy and system of practice based on the European nature cure movement that flourished in the 1800s. At the core of this philosophy was the vis medicatrix naturae (healing power of nature) and the naturalistic concept of vitalism. As such, naturopathic medicine has deep historical roots and represents a lineage of Western natural medicine that can be traced back to the Roman, Greek, Egyptian, and Mesopotamian cultures and, conceptually, to many traditional and indigenous world medicines. The modern naturopathic profession originated with Lust, and it grew under his tireless efforts. He crisscrossed the United States, lecturing and lobbying for legislation to license naturopathy, testifying for naturopaths indicted for practicing medicine without a license, and traveling to many events and conferences to help build the profession. He also wrote extensively, including two monthly newspapers (The Naturopath and Herald of Health) for nearly 40 years, to foster and popularize the profession, and through his efforts, the naturopathic profession grew rapidly.2–4 By the 1940s, naturopathic medicine had developed a number of 4-year medical schools and had achieved licensure in about one third of the United States, the District of Columbia, four Canadian provinces, and a number of other countries.3,5 *Previous edition contributor

11

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a culture that turned to mechanistic science as an unquestioned authority. The dawning of the atomic age reinforced a fundamental place for science in a society increasingly dominated by scientific discovery. In this culture, standard medicine, with its growing political and economic strength, was able to force the near elimination of naturopathic medicine through the repeal or “sunsetting” of licensure acts.2,3,12 In 1956, as the last early doctor of naturopathy (ND) educational program ended (at the Western States College of Chiropractic), several doctors, including Drs. Ralph Weiss, Charles Stone, W. Martin Bleything, and Frank Spaulding, created the National College of Naturopathic Medicine in Portland, Oregon, to keep the profession alive. However, that school was nearly invisible as the last vestige of a dying profession and rarely attracted as many as 10 new students a year. The profession was considered dead by its historical adversaries. The culture of America, dominated by standard medicine since the 1940s, however, began to change by the late 1960s. The promise of science and antibiotics was beginning to seem less than perfect. Chronic disease was increasing in prevalence as acute infection was becoming less predominant, and standard medicine had no “penicillin” for chronic diseases. In the late 1970s, scholars in family medicine proposed a biopsychosocial model of care in response to a prevailing perception of a growing crisis in standard medicine.13 The publication of Engel’s “The Need for a New Medical Model” in April 1977 signaled the founding of the field of family medicine based on a holistic philosophy. This shifting culture within standard medicine paralleled a broader social movement in support of alternative health practices and environmental awareness. Elements of the culture were rebelling against plastics and cheap synthetics, seeking more natural solutions. The publication of Rachael Carson’s Silent Spring in 1962, an indictment of chemical pesticides and environmental damage, marked a turning point in cultural thinking. In Silent Spring, Carson challenged the practices of agricultural scientists and the government and called for a change in the way humankind viewed the natural world.14 New evidence of the dangers of radiation, synthetic pesticides, and herbicides and environmental degradation from industrial pollution was creating a new ethic. Organic farming, natural fibers, and other similar possibilities were starting to capture attention. A few began seeking natural alternatives in medicine. By the late 1960s and early 1970s, enrollments at the National College of Naturopathic Medicine began to reach into the 20s. The 1974 class numbered 23 students. In 1975 the National College enrolled a class of 63 students.15 The profession was experiencing a resurgence. In 1978, with a desire to create a college based on science-based natural medicine, Joseph E. Pizzorno, ND, LM, and his colleagues—Les Griffith, ND, LM; Bill Mitchell, ND; and Sheila Quinn—created the John Bastyr College of Naturopathic Medicine in Seattle, Washington. With the creation of Bastyr, named after the eminent naturopathic physician Dr. John Bartholomew Bastyr (1912–1995), the profession entered a new phase. Not only did this new college double the profession’s capacity to produce new doctors, but it also firmly placed the profession on the ground of scientific research and validation. “Science-based natural medicine,” coined by Dr. Pizzorno, was a major driving force behind the creation and mission of Bastyr. Both Drs. Bastyr and Pizzorno had significant influence and leadership in achieving this focus. One of Dr. Bastyr’s important legacies was to establish a foundation and a model for reconciling the perceived conflict between science and the deeply established healing practices and principles of naturopathic medicine. Kirchfeld and Boyle4 described his landmark contribution as follows: Although naturopathic colleges in the early 1900s did include basic sciences training, it was not until Dr. John Bastyr (1912–1995) and his firm, efficient and professional leadership that science and

research-based training in natural medicine was inspired to reach its fullest potential. Dr. Bastyr, whose vision was one of “naturopathy’s empirical successes documented and proven by scientific methods,” was himself the prototype of the modern naturopathic doctor, who culls the latest findings from the scientific literature, applies them in ways consistent with naturopathic principles and verifies the results with appropriate studies. Bastyr also saw a tremendous expansion in both allopathic and naturopathic medical knowledge, and he played a major role in making sure the best of both were integrated into naturopathic medical education.4,16 Bastyr met Lust on two occasions and was closely tied to the nature cure tradition of Kneipp through two influential women: his mother, and his mentor, Dr. Elizabeth Peters, who studied with Father Kneipp. He effortlessly integrated the clinical theories and practices of naturopathy with the latest scientific studies and helped create a new and truly original form of modern primary clinical care within naturopathic medicine. He spent the 20th century preparing the nature cure of the 19th century for entry into the 21st century.2,16 Today’s philosophic debates within the profession are no longer about science. They now tend to center on both sides of the earlier debate and include challenges to the nature cure tradition. A current debate, for instance, is about the role of “green allopathy” within the profession: the tendency to use botanical medicine or nutritional supplements as a simple “green drug” or pharmaceutical replacement therapy. This is in contrast to implementing the full range of healing practices derived from the nature cure tradition and within the framework of the therapeutic order construct to stimulate health restoration as the foundation for reversing disease, alongside, or instead of, botanical medicine or nutritional supplements. Professional consensus appears strong that the full range of naturopathic healing practices must be retained, strengthened, and engaged in the process of education and scientific research and discovery in the 21st century.17–19 

ORIGINAL PHILOSOPHY AND THEORY Through the initial 50-year period of professional growth and development (1896–1945), naturopathic medicine had no clear and concise statement of identity. The profession was whatever Lust said it was. He defined “naturopathy” or “nature cure” as both a way of life and a concept of healing that used various natural means of treating human infirmities and disease states. The “natural means” were integrated into naturopathic medicine by Lust and others based on the emerging naturopathic theory of healing and disease etiology. The earliest therapies associated with the term involved a combination of American hygienics and Austro-Germanic nature cure and hydrotherapy. Leaders in this field included Kuhne, Lindlahr, Trall, Kellogg, Holbrook, Tilden, Graham, McFadden, Rikli, Thomson, and others who wrote foundational naturopathic medical treatises or developed naturopathic clinical theory, philosophy, and texts to enhance, agree with, and diverge from Lust’s original work.20–28 The bulk of professional theory was found in Lust’s magazines, Herald of Health and The Naturopath. These publications displayed the prodigious writings of Lust but did not contain a comprehensive and definitive statement of either philosophy or clinical theory. Lust often stated that all natural therapies fell under the purview of naturopathy. Several texts were considered as somewhat definitive by various aspects of the profession at different times. These texts included Adolph Just’s Return to Nature (1896), Louis Kuhne’s The New Science of Healing (1899), and the seven-volume Natural Therapeutics by Henry Lindlahr, MD, which was published in the early 1900s. Lindlahr’s Nature Cure (1913) was considered a seminal work in naturopathic theory, laying

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A Hierarchy of Healing: The Therapeutic Order

the groundwork for a systematic approach to naturopathic treatment and diagnosis. Lindlahr ultimately presented the most coherent naturopathic theory extant, summarized in his Catechism of Nature Cure, which presented a five-part therapeutic progression: 1. “Return to nature”—attending to the basics of diet, dress, exercise, rest, etc. 2. Elementary remedies—water, air, light, electricity 3. Chemical remedies—botanicals, homeopathy, etc. 4. Mechanical remedies—manipulations, massage, etc. 5. Mental/spiritual remedies—prayer, positive thinking, doing good works, etc.29 Lindlahr’s five-step therapeutic progression follows the Catechism’s disease causation model: “The primary cause of disease, barring accidental or surgical injury to the human organism and surroundings hostile to human life, is violation of Nature’s Laws.” The effects of violation of nature’s laws on the physical human organism are also the primary causes of disease because they inhibit normal function, lower vitality, and result in tissue destruction: Primary Lowered vitality Abnormal composition of blood and lymph Accumulation of waste, morbid matter, and poisons in the system Secondary Hereditary/constitutional Fevers, inflammation Mechanical luxations Weakening and loss of reason, will, etc.29 In 1948 Spitler wrote Basic Naturopathy, a Textbook,10 and in 1951 Wendel wrote Standardized Naturopathy.11 These texts presented somewhat different approaches; Spitler’s text emphasized theory and philosophy, whereas Wendel’s text was written, as evidenced by the title, to emphasize the standard naturopathic practices of the day, with an eye toward regulatory practice. In contrast, Kuts-Cheraux’s Naturopathic Materia Medica, written in 1953, was produced to satisfy a statutory demand by the Arizona legislature but persisted as one of the few extant guides of that era. Practitioners relied on a number of earlier texts, many of which arose from the German hydrotherapy practitioners30–35 or the eclectic school of medicine (a refinement and expansion of the earlier “Thomsonian” system of medicine)36–40 and predated the formal American naturopathic profession (1900). However, by the late 1950s, publications diminished. The profession was generally considered on its last gasp, an anachronism of the preantibiotic era. During the process of winning licensure, naturopathic medicine was defined formally by the various licensure statutes, but these definitions were legal and scope-of-practice definitions, often in conflict with each other, reflecting different standards of practice in different jurisdictions. In 1965 the U.S. Department of Labor’s Dictionary of Occupational Titles41 presented the most formal and widespread definition. The definition was not without controversy because it reflected one of the internally competing views of the profession, primarily, the nature cure perspective: Diagnoses, treats and cares for patients using a system of practice that bases treatment of physiological function and abnormal conditions on natural laws governing the human body. Utilizes physiological, psychological and mechanical methods such as air, water, light, heat, earth, phytotherapy, food and herbs therapy, psychotherapy, electrotherapy, physiotherapy, minor and orificial therapy, mechanotherapy, naturopathic corrections and manipulations, and natural methods or modalities together with natural medicines, natural processed food and herbs and natural remedies. Excludes major surgery, therapeutic use of x-ray and radium, and

13

the use of drugs, except those assimilable substances containing elements or compounds which are components of body tissues and physiologically compatible to body processes for the maintenance of life.41 This definition did not list drugs or surgery within the scope of modalities available to the profession. It defined the profession by therapeutic modality and was more limited than most of the statutes under which naturopathic physicians practiced,42 even in 1975, when there were only eight licensing authorities still active. 

MODERN NATUROPATHIC CLINICAL THEORY: THE PROCESS OF DEVELOPMENT Medical philosophy comprises the underlying premises on which a health care system is based. Once a system is acknowledged, it is subject to debate. In Naturopathic medicine, the philosophical debates are a valuable, ongoing process which helps the understanding of health and disease evolve in an orderly and truth-revealing fashion. Randall Bradley, ND43 After the profession’s decline in the 1950s and 1960s, a rebirth was experienced, more grounded in medical sciences and fueled by a young generation with few teachers. The profession’s roots were neglected out of ignorance, for the most part, along with a youthful arrogance. By the early 1980s, it was apparent that attempts to regenerate the progress made by Lust would require the creation of a unified professional organization and all which that entailed: accreditation for schools, national standards in education and licensure, clinical research, and the articulation of a coherent definition of the profession for legislative purposes, as well as for its own internal development. These accomplishments would be necessary to be able to demonstrate the uniqueness and validity of the profession, guide its educational process, and justify its status as a separate and distinct medical profession. In 1987 the newly formed (1985) American Association of Naturopathic Physicians (AANP) began this task of developing a unified professional organization under the leadership of James Sensenig, ND (president), and Cathy Rogers, ND (vice president). Four tasks were developed, and committees with specific chairs were delegated. One task was to pursue accreditation of our schools through governmental accreditation bodies, headed by Joe Pizzorno, ND. Another was to create a standard, national licensure examination, independent of the profession, headed by Edwin Smith, ND. A third was to create a peer-reviewed journal that the profession could use to demonstrate its rational basis, headed by Peter D’Adamo, ND. The fourth was a committee to head the creation of a new definition of naturopathic medicine headed by Pamela Snider, ND, and Jared Zeff ND, LAc. The “Select Committee on the Definition of Naturopathic Medicine” succeeded in its 3-year project, which culminated in the unanimous adoption by the AANP’s House of Delegates (HOD) of a comprehensive, consensus definition of naturopathic medicine in 1989 at the annual convention held at Rippling River, Oregon.44–46 The unique aspect of this definition was its basis in definitive principles, rather than therapeutic modalities, as the defining characteristics of the profession. In passing this resolution, the HOD also asserted that the principles would continue to evolve with the progress of knowledge and should be formally reexamined by the profession as needed, perhaps every 5 years.44–49 In September 1996 the AANP HOD passed a resolution to review three proposed principles of practice that had been recommended as

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additions to the AANP definition of naturopathic medicine originally passed by the HOD in 1989. These three new proposed principles were rejected, and the AANP HOD reconfirmed the 1989 AANP definition unanimously in 2000. The results of a profession-wide survey conducted from 1996 to 1998 on these three new proposed principles demonstrated that although there was lively input, the profession agreed strongly that the original definition was accurate and should remain intact. The HOD recommended that the discussion be moved to the academic community involved in clinical theory, research, and practice for pursuit through scholarly dialogue.50–54 This formed the basis for further efforts to articulate a clinical theory. AANP members stated in 1987 to 1989 during the definition process: “These principles are the skeleton, the core of naturopathic theory. There will be more growth from this foundation.”46 By 1997, this growth in modern clinical theory was evident. The first statement of such a theory was published in the AANP’s Journal of Naturopathic Medicine in 1997 in an article titled “The Process of Healing, a Unifying Theory of Naturopathic Medicine.”55 This article contained three fundamental concepts that were presented as an organizing theory for the many therapeutic systems and modalities used within the profession and were based on the principles articulated in the consensus AANP definition of naturopathic medicine. The first of these was the characterization of disease as a process rather than a pathological entity. The second was the focus on the determinants of health rather than on pathology. The third was the concept of a therapeutic hierarchy. This article also signaled the emergence of a growing dialogue among physicians, faculty, leaders, and scholars of naturopathic philosophy concerning theory in naturopathic medicine. The hope and dialogue sparked by this article were the natural next step of a profession redefining itself both in the light of today’s advances in health care and with respect to the foundations of philosophy at the traditional heart of naturopathic medicine. This dialogue naturally followed the discussions of the definition process and created a vehicle for emerging models and concepts to be built on the bones of the principles. The essence and inherent concepts of traditional naturopathic philosophy were carried in the hearts and minds of a new generation of naturopathic physicians into the 21st century— these modern naturopathic students and naturopathic physicians began to gather to articulate, redefine, and reunify the heart of the medicine. This new dialogue was formally launched in 1996, when the AANP Convention opened with the plenary session “Towards a Unifying Theory of Naturopathic Medicine,” with four naturopathic physicians presenting facets of emerging modern naturopathic theory. The session closed with an open microphone. The impassioned and powerful comments of the naturopathic profession throughout the United States and Canada engaged in the vital process of deepening and clarifying its unifying theory. Dr. Zeff presented “The Process of Healing: The Hierarchy of Therapeutics”; Dr. Mitchell presented “The Physics of Adjacency, Intention, Naturopathic Medicine, and Gaia”; Dr. Sensenig presented “Back to the Future: Reintroducing Vitalism as a New Paradigm”; and Dr. Snider announced the Integration Project, inviting the profession to engage in it by “sharing a beautiful and inspiring anguish—the labor pains of naturopathic theory in the twenty-first century. We know what we have done, and we know there is much more…The foundation is laid. We are ready now for development and integration.”56 Days later, in September 1996, the Consortium of Naturopathic Medical Colleges (now the American Association of Naturopathic Medical Colleges [AANMC]) formally adopted and launched the Integration Project, an initiative to integrate naturopathic theory and

philosophy throughout all divisions of all naturopathic college curricula, from basic sciences to clinical training. A key element of the project engaged the further development and refinement of naturopathic theory. The project was cochaired by Drs. Snider and Zeff from 1996 to 2003. Steering members from all North American naturopathic colleges participated and contributed.46 Methods included professional and scholarly research, expert teams, symposiums, and training. The result was the fostering of systematic inquiry among academicians, clinicians, and researchers concerning the underlying theory of naturopathic medicine, bringing the fruits of this work and inquiry into the classroom and into scientific discussion.57 The Integration Project sustained both formal and informal dialogue since its inception in 1996, which continues today through the Foundations of Naturopathic Medicine Institute. The work has engaged faculty and scholars of naturopathic philosophy in the United States, Canada, the United Kingdom, Australia, and many other countries where naturopathy is established or is professionalizing. It has also engaged institutional leaders and practicing doctors and faculty in all areas of the profession. Why? Naturopathic philosophy is deeply felt as the “commons” of naturopathic medicine: a place where the profession meets—one that is owned by all naturopathic physicians—that reflects, holds, and deepens the heart of naturopathic medicine. The philosophy of naturopathic medicine is the foundation and heart of naturopathic medicine and consists of its heritage, knowledge base, concepts, and knowledge codification; its clinical decision making; its integration and initiation of scientific research; and its public policy positions. The philosophy remains valid by evolving with the progress of knowledge, the progress of science, and the progress of the human spirit. It is for this reason medicine is seen as an art and a science. Because naturopathic philosophy engages the intuitively felt mission of nature doctors, it is vital that the profession periodically gathers to renew and revitalize progress regarding its unifying foundations. The Integration Project sparked a wide range of activities in all six ND colleges at that time, resulting in all-college retreats to share tools, retreats for training of non-ND faculty in naturopathic philosophy, integration of a basic sciences curriculum, expert-team revision of core competencies across departments ranging from nutrition to case management and counseling, development of clinical tools and seminars for clinic faculty, creation of new courses, and the integration of important research questions derived from naturopathic philosophy into research studies and initiatives.58 The latest effort, the Foundations of Naturopathic Medicine Institute and Project (textbook codification and symposia series; see www.foundationsproject.com) includes its development and presentation of the founding educational module on emunctorology, an essentially naturopathic science, during 2009 and 2010. This is a joint effort of faculty from several of our schools, led by Drs. Thom Kruzel, Rita Bettenberg and Stephen Myers. North American core competencies for naturopathic philosophy and clinical theory were developed by faculty representing all accredited ND colleges in a landmark AANMC retreat in 2000. The AANMC’s Dean’s Council formally adopted these competencies in 2000 and recommended that they be integrated throughout curricula in all ND colleges. These national core competencies included the process of healing theory, Lindlahr’s model, and the hierarchy of therapeutics (the therapeutic order).59,60 Finally, many meetings with scholars and teachers of naturopathic theory and other faculty and leaders—formal and informal—resulted in the further development and refinement of the hierarchy of therapeutics developed by Dr. Zeff in 1997. Drs. Snider and Zeff and worked closely with each other and then with other naturopathic theory faculty from AANMC colleges in a

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BOX 2.1  Working Definition of Naturopathic

Nutrition

Consensus Statement from Naturopathic Nutrition Faculty Retreat, Naturopathy and Nutrition Panel and Southern Cross University, June 2003, Preamble Naturopathic medicine is a distinct system of primary health care—an art, science, philosophy and practice of diagnosis, as well as treatment and prevention of illness. Naturopathic medicine is distinguished by the principles that underlie and determine its practice. These principles include the healing power of nature (vis medicatrix naturae), identification and treatment of the causes (tolle causam), the promise to first do no harm (primum non nocere), doctor as teacher (docere), treatment of the whole person, and emphasis on prevention. These principles give rise to a practice that emphasizes the individual and empowers him or her to greater responsibility in personal health care and maintenance. Definition Naturopathic nutrition is the practice of nutrition in the context of naturopathic medicine. Naturopathic nutrition integrates both scientific nutrition and the principles of naturopathic medicine into a distinct approach to nutritional practice. Core components of naturopathic nutrition are: Respect for the traditional and empirical naturopathic approach to nutritional knowledge The value of food as medicine An understanding that whole foods are greater than the sum of their parts and recognition that they have vitality (properties beyond physiochemical constituents) Individuals have unique interactions with their nutritional environments  Practice In the context of the definition, and with respect to the therapeutic order, the practice of naturopathic nutrition may include the appropriate use of the following: Behavioral and lifestyle counseling Diet therapy (including health maintenance, therapeutic diets, and dietary modification) Food selection, preparation, and medicinal cooking Therapeutic application of foods with specific functions Traditional approaches to detoxification Therapeutic fasting strategies Nutritional supplementation

series of revisions. Drs. Snider and Zeff collaborated in 1998 to develop the hierarchy of therapeutics into the “therapeutic order.” The therapeutic order was subsequently explored and refined through a series of faculty retreats and meetings, as well as through experience with students and through student feedback. A key finding of the clinical faculty at Bastyr University was the emphasis on the principle “holism: treat the whole person” and respect for the patient’s own unique healing order and his or her values as a context for applying the therapeutic order to clinical decision making.61 The therapeutic order, or hierarchy of healing, is now incorporated into ND college curricula throughout the United States, Canada, Australia, and New Zealand. For example, an important international outgrowth of the profession’s development of theory is the adoption of the unified “Working Definition of Naturopathic Nutrition” in June 2003 by the Australian naturopathic profession (Box 2.1). The 3-year project, fostered by Dr. Stephen Myers, brought together nutrition faculty from naturopathic medicine colleges throughout Australia. The project was cohosted by the Naturopathy and Nutrition Panel, an independent group of naturopaths and nutrition educators whose mission is to foster and support

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the development of the science, teaching, and practice of naturopathic nutrition, and the School of Natural and Complementary Medicine at Southern Cross University. The definition evolved over two retreats attended by more than 40 faculty members involved in teaching nutrition as part of a naturopathic medicine education. It commenced as a general agreement within the group that there was a real and distinct difference between conventional nutritional concepts and naturopathic nutritional theory. The general agreement was that the distinction between the two had been poorly defined to date and had been the source of dissonance between the naturopathic and science faculty within the colleges. The obvious next step was to define that difference to ensure that nutrition curriculum within naturopathic medicine colleges reflected the core elements of naturopathic nutrition. At the second retreat held in June 2003, the working definition was adopted with a recommendation that it be widely circulated within the naturopathic medicine profession to commence a dialogue aimed at both appropriate revision and broad adoption. This process created a much-needed consensus definition of naturopathic nutrition. This definition is based on the AANP defining principles and incorporates the therapeutic order theory. The AANP Definition of Naturopathic Medicine position paper was reviewed again in 2010 and reratified unanimously in 2011 by the AANP House of Delegates. “Prescription medications” were added to the single Treatment and Care section and both Naturopathic Practice sections in the 5-page paper (see www.naturopathic.org). In 2015 the World Naturopathic Federation, founded in 2015, published its first international survey results on naturopathic medicine’s core concepts and education in two white papers: The World Naturopathic Federation Report: Findings From the 1st World Naturopathic Federation Survey (2015) and WNF White Paper: Philosophies, and Principles, Theories (2017). The therapeutic order was reported in the top three (2015) and top five (2017) theory concepts utilized by the profession across the world. The results of the 2015 report stated that the AANP Definition of Naturopathic Medicine position paper and its six principles were widely accepted as written by professionalizing naturopaths in countries responding to the survey, at an average rate of 95%.62–65 

A THEORY OF NATUROPATHIC MEDICINE Standard medicine, or biomedicine, has a simple and elegant paradigm. Simply stated, it is “the diagnosis and treatment of disease.” In practice, this statement contains several assumptions. One assumption is that illness can be understood in terms of discrete diseases (i.e., human illnesses can be divided into identifiable entities, such as measles or specific forms of cancer, etc.). The next assumption is that “cure” is the elimination of the disease entity. The third assumption is that this is accomplished by the evidence-based application of pharmaceuticals, surgeries, or similar treatments to eliminate, palliate, or suppress the entity and its symptomatic expressions. These are so obvious that they are not commonly considered. They form the background thinking in medical decision making: “identify and treat the disease.” The elegance of this model, and the science behind it, has taken standard medicine to its highest point in history as a reliable vehicle to ease human illness, and its application has saved countless lives. The understanding of the physician, at least about the nature of pathology, has never been as complete as now. However, illness has a near-infinite capacity to baffle the physician. New diseases arise, such as Legionnaire’s disease, human immunodeficiency virus/acquired immune deficiency syndrome, and Lyme disease, and shifts occur in disease focus, such as the shift between 1900 and 2000 from acute infection to chronic illness as the predominant cause of death.66

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Beyond these obvious changes, even with the current depth of understanding, the standard medical world often lacks the ability to effectively understand and cure chronic disease, and treatment tends to become a task of the management of symptoms and the attempt to reduce long-term damage and other consequences rather than actual cure of the illness. So, even representing an apex of human achievement as it does, standard medicine is not without its weaknesses. Its greatest weaknesses include its relatively high cost,67 its tendency to create iatrogenic disease,67 and its inability to cure chronic illness as easily as it once cured pneumonia with penicillin or tuberculosis with streptomycin. Compounding the problem is the growing prevalence of antibiotic-resistant infections.68,69 Part of the reason for the failures within biomedical science is its mechanistic basis. Breaking the body down to its constituent parts has led to a fundamental ignorance of and disrespect for the wholeness of the individual, the natural laws of physiology governing health and healing, and particularly for all things spiritual (the transpersonal domains). Inherent in the dictum—diagnose and treat the disease—is the general neglect of the larger understanding that disease is a process conducted by and within an intelligent organism that is constantly attempting to heal itself, with disease manifestations often being expressions of this self-healing endeavor. As noted by Pizzorno et al.,70 this intelligent organism strives for optimal function and health. Human beings “are natural organisms, our genomes developed and expressed in the natural world. The patterns and processes inherent in nature are inherent in us. We exist as a part of complex patterns of matter, energy, and spirit. Nature doctors have observed the natural processes of these patterns in health and disease and determined that there is an inherent drive toward health that lives within the patterns and processes of nature.” The uniqueness of naturopathic medicine is not in its therapeutic modalities or the “natural” alternatives to the drugs and surgeries of standard medicine. It is the clinical theory that governs the selection and application of these modalities, captured in the unifying definition adopted in 1989 and expressed more specifically in the continuing articulation of clinical theory. That is, it is the way the naturopathic physician thinks about illness and healing. The first element of this theory is based on the first defining principle: vis medicatrix naturae. It is based on the understanding that disease can be seen as a process and an entity. One can analyze the process of illness and derive some understanding. However, to do this, one needs to examine the assumptions underlying this concept. The governing assumptions of standard medicine are principally that diseases are entities and that drugs and surgery can eliminate these entities from the suffering person. These are not the governing assumptions of naturopathic medicine.

Illness and Healing as Process Naturopathic medicine can be characterized by a different model than “identify and treat the disease.” “The restoration of health” would be a better characterization. Naturopathic physicians adopted the following elegantly brief definition of naturopathic medicine in 1989 in an AANP position paper: “Naturopathic physicians treat disease by restoring health.”45 Immediately, a significant difference is made clear: standard medicine is disease based; naturopathic medicine is health based. Although naturopathic medical students study pathology with the same intensity and depth as standard medical students, as well as its concomitant diagnoses, the naturopathic medical student learns to apply that information in a different context. In standard medicine, pathology and diagnosis are the basis for the discernment of the disease “entity” that afflicts the patient, the first of the two steps of identifying and destroying the entity of affliction. In naturopathic medicine, however, disease is seen much more as a process than as an entity. Rather

The Process of Healing Optimal health

Normal health Disturbing factors Disturbance of function

Discharge Process

Reaction (inflammation, fever, etc.)

Chronic reaction

Degeneration (ulceration, atrophy, scar, paralysis, tumor, etc.) Fig. 2.1  The process of healing. Copyright 1997. (Used by permission. Jared L. Zeff, ND, LAc.)

than viewing the ill patient as experiencing a “disease,” the naturopathic physician views the ill person as functioning within a process of disturbance and recovery, in the context of nature and natural systems. Various factors disturb normal health. If the physician can identify these disturbances and moderate them (or at least some of them), the illness and its effects abate. As disturbances are removed, the body can improve in function, and in doing so, health naturally improves. The natural tendency of the body is to maintain itself in as normal a state of health as is possible—this is the basis of homeostatic principles.71 The role of the physician facilitates this self-healing process. The obvious first task of the naturopathic physician, therefore, is to determine what is disturbing the health so that these causative elements may be ameliorated. Disease is the process whereby the intelligent body reacts to disturbing elements. It employs such processes as inflammation and fever to help restore its health. In general, one can graph this process simply, as in Fig. 2.1. 

The Naturopathic Model in Acute Illness One can see “illness as process” most easily in the common cold. Within standard medical understanding, the common cold is caused by a virus, from among a family of pathological viruses that can infect a person. The immune system responds, developing appropriate antibodies, which eventually neutralize the virus. There is no “cure” yet discovered, except time. Medications are used to ameliorate the symptomatic experience: aspirin or acetaminophen for fever, decongestants to dry the mucus discharge, and so forth. These measures are not cures; they reduce the symptomatic expression of the “cold” but often lengthen the process. In naturopathic medicine, the cold is seen not as a disease entity but as part of a fundamental process whereby the body restores itself to health. If the virus were the sole cause of the common cold, then everyone who came into contact with a sufficient dose of the virus would get the cold. Obviously, this does not happen. Susceptibility factors include immune competence, fatigue, vitality, genetics, and other host factors.72 The virus enters a milieu in which all these factors affect the process. Once the virus enters the system, and if it overcomes resistance factors (Box 2.2), one begins to see disturbance of function, as illustrated in Fig. 2.1. One does not feel quite right. One may

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BOX 2.2  Scientific Considerations: The

BOX 2.4  Scientific Considerations: The Role

Once inside the body, the rhinovirus binds to cellular receptors (primarily the intercellular adhesion molecule-1 [ICAM-1]) or to the low-density lipoprotein (LDL) receptor. The viral particles are then internalized and begin to take over the cellular machinery to produce intact virions.72,103 At this stage, the body can sometimes mount an adequate defense via cell-mediated immunity to overcome the viral incursion. If we have been previously exposed to the virus, the body’s humoral immune response will rapidly produce antibodies to the viral protein, which can also lead to eradication of the microbe. These two immune responses explain why some individuals may develop the full condition, whereas others will shake off the exposure within a few hours. If the viral load overcomes the body’s innate defenses, the virus replicates unabated. In the process of replication, the virus not only disrupts the cellular mechanisms but also damages them as well by infecting the surface epithelium and the macrophages104 and fibroblasts.105 Naturopathic physicians are interested in the factors that lead to greater immune competence and health restoration through the process of healing and the health practices that support it. French physiologist Claude Bernard (1813–1878) said that the inner terrain or “milieu interieur” was the cause of disease, not the microbes; this concept underpins the naturopathic approach.

Environmental and lifestyle disturbances are a profound driver in the naturopathic model of health. The scientific evidence is now irrefutable that the national and global burden of chronic disease is highly dependent on modifiable behavioral factors. In a recent study of the causes of death, it was found that tobacco, poor diet and lack of physical activity, alcohol and drug use, toxic agents, and vehicular and firearm incidents were the leading actual causes of death.76 Other factors included frank malnutrition (as opposed to poor nutrition), unsafe sexual practices, and poor sanitation.77,78 It has been definitively shown, for example, that diet and lifestyle changes can prevent some forms of diabetes101,102 and other chronic diseases142,143 that are leading causes of death in the United States.76,101,102

Immune Response and Resistance Factors

BOX 2.3  Scientific Considerations: Consequences of Suppressing the Body’s Response Current research shows that future pathologies may be linked to “suppression” of early rhinovirus infection. These include childhood asthma, adult asthma, and chronic obstructive pulmonary disease (COPD).106,107 Individuals with asthma are known to have subtle deficiencies in production of type I and type III interferon (IFN),108,109 indicating that for some asthma patients, early exposure to the rhinovirus predisposes them to asthma, and that the suppression of the normal response may be critical in the future development of asthma. With these effects in mind, the naturopathic physician does not look solely at the virus as a pathogenic entity but also seeks to determine how the patient responds to the virus, thereby determining the most reasonable approach to aiding the patient’s natural responses and moderating the patient’s long-term health strategies. Suppression of the body’s natural responses is avoided. The long-term use of corticosteroids is a prime example of suppression and its consequences.137,140

begin to get a sore throat, the first inflammatory reaction, occurring at the point of entry of the virus into the body. The immune factors described may overcome the virus at this point, may be insufficient, or may be suppressed. All of this is mutable to some extent and is affected by host factors, such as nutritional status and fatigue, and can be influenced by taking immune tonics, vitamin C, and other supplements. To the individual with the condition, the “cold” may proceed into a general state of fatigue and inflammation, possibly fever followed by mucus discharge, cough, and other symptoms, as the body processes and responds to the virus and its effects; eventually, the body overcomes it and eliminates the results. In the naturopathic model, the cold is not understood so much to be a separate disease entity but a general and fundamental process of disturbance and recovery within the living body. It is a method whereby the body restores itself after a sufficient amount of disturbance accumulates within the system. This is why the cold has no “cure.” It is the cure for what ails the body. In the naturopathic model of health, it is the support of this “adaptive response”—the restoration of balance that is the central point—through which the process is the “cure” (Box 2.3).

of Environment in Chronic Illness

The early naturopathic philosophers and clinicians predicted that the treatment of acute disease by suppressing symptoms (discussed in more depth later in the chapter) would result in more chronic disease. The current disease burden in the Western world certainly confirms this century-old prediction. 

The Naturopathic Model in Chronic Illness Chronic illness arises, in general, when any or all of three factors occur: 1. The disturbing factors persist, such as a chronically improper diet, which continues to burden the body cumulatively, as the digestive processes slowly weaken under the stress of the improper or inadequate diet. 2. The reactive potential is blocked or suppressed, often by drugs, which interfere with the capacity of the body to process and remove its disturbances. 3. The vitality of the system is insufficient, or has become too overwhelmed, to mount a significant and sufficient reaction. Again, as Lindlahr stated in Nature Cure, Chapters 2 and 4, disease is caused by one or more of the following as a result of violating nature’s laws of healthy living: Lowered vitality Abnormal composition of blood and lymph Accumulation of morbid matter and poisons As any of these factors either continue to accumulate and disturb function or reduce the ability of the body to purge the disturbance, the body slides into a chronic, weakened reactive state, with possible episodes of intermittent reaction, and is perceived to be in a persistent chronic illness. Ultimately, as function is sufficiently disturbed, structures or functions are damaged, and chronic inflammation becomes ulceration or scar tissue formation. In terms of the allostatic model, the balance has been disrupted, and there is no more adaptive potential. Atrophy, paralysis, or even tumor formation73–75 may occur. All of this is the body manifestly doing the best it can for itself in the presence of persistent disturbing factors and with respect to the limitations and range of vitality influenced by the constitution, psycho-emotional/spiritual state, and genotype of the person and his or her surrounding environment (Boxes 2.4 and 2.5). Reversal of this overwhelmed condition is rarely accomplished by medicating the pathological state. This often results in the control of symptoms but with the persistence of the illness while ideally controlling its more dangerous aspects using higher force interventions, such as pharmaceutical drugs and surgical intervention. Reversal is more likely accomplished by identifying and ameliorating the disturbance and, as necessary, strengthening or supporting the individual response or reactive potential. The first step in this process is to identify and reduce disturbing factors. 

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BOX 2.5  Scientific Considerations: Chronic

Illness and the Adaptive Response

Regarding the responses of an overwhelmed or chronically disturbed organism, it has been argued recently that the anemia of chronic disease is an adaptive biological response rather than a harmful disorder and is associated with a number of chronic states.92 Citing a number of studies, it was also argued that it was the treatment of the anemia of chronic disease among critically ill patients and those with renal failure and cancer (e.g., breast cancer and head and neck cancers) that was associated with the greater mortality. The U.S. Food and Drug Administration issued a warning against the use of erythropoiesis-stimulating agents in those cancer patients not undergoing chemotherapy or radiation therapy.143 States where the normal compensatory mechanisms become overwhelmed or suppressed (reducing the reactive potential of the body) include states of chronic oxidative stress144 and inflammatory processes.145,146 It is not, however, solely a matter of an overwhelmed or chronically disturbed organism that is critical to the process of disease progression. Adaptive responses are also of vital importance to the development of chronic disease. Research has shown that these evolutionarily preserved adaptive mechanisms of physical activity, insulin sensitivity, and fat storage are essential in the prevention of chronic disease states.141,142 In the development of type 2 diabetes, for example, there is increasing evidence that it is the individual’s maladaptation to lack of physical activity that appears to lead to decreased insulin sensitivity and increased fat storage, which can then lead to a plethora of chronic diseases, many characterized by states of chronic inflammation147 and oxidative stress. Continuing basic and clinical studies indicate that many of the processes currently regarded in mainstream medicine as harmful have been evolutionarily retained to provide an adaptive advantage.148,149 The Harvard Health Letter recently published an article describing inflammation as part of the “Unifying Theory of Disease”150 giving support to the argument that inflammation is crucial in both health and disease and that chronic diseases arise when the inflammatory process occurs without appropriate control. The allostatic model also provides a theoretical basis for naturopathic clinical theory. The allostatic model describes the process of achieving stability (homeostasis) through changes in the homeostatic “set points” or control boundaries.82–85 Homeostasis, the maintenance of stability in biochemical and physiological processes, is essential for life—and allostasis, the “resetting” of the homeostatic “set points,” is essential for the maintenance of homeostasis. As it develops through the various iterations of researchers and clinicians, the model emphasizes the need to look beyond the current linear-reductionist model of disease and toward a more holistic and balanced approach to disease conditions. The adaptive response of the organism to insult or frank structural damage is a concept that also has support outside naturopathic medicine. For example, Schnaper et al.151 described a conceptual framework for progressive kidney disease where the initial disease develops through an injury of some nature that provokes a cellular response as an adaptation to the original injury. Where this cellular response is effective, no progressive kidney disease may ensue. If, however, there is a maladaptation, these attempts at self-repair may lead to progressive loss of nephrons and chronic kidney disease.

THE DETERMINANTS OF HEALTH To reduce the disturbance, one must identify the disturbance. In standard medicine, the first step is to identify the pathology, which is then treated. In naturopathic medicine, one must come to understand what is disturbing the health. To do this, the physician needs to understand what determines health in the first place. The physician can then evaluate the patient in these terms and come to understand what is disturbing the natural state of health. Such a list could be created by any doctor, certainly any naturopathic physician. The authors propose the use of the list in Box 2.6.

Some of these determinants have been discussed—those modifiable behavioral factors such as drug and alcohol use, poor diet or frank malnutrition, lack of physical exercise, environmental and socioeconomic factors, and unsafe sexual practices76–79 (Box 2.7). Many of these behavioral factors have major psychological and spiritual components, and the effect can be increased stress on both the individual and the family, with all its attendant consequences.79–81 The naturopathic physician evaluates the patient with these areas in mind, looking for aspects of disturbance, first in the spirit and most generally in diet, digestion, and stress in its various aspects. In this evaluation, the naturopathic physician brings to bear a body of knowledge somewhat unique to naturopathic medicine to evaluate not solely in terms of pathological entity but also in terms of normal function and subclinical functional disturbance (Box 2.8). By locating areas of abnormal function or disturbance, the naturopathic physician acts or recommends ways to ameliorate the disturbance. As disturbing factors or insults to the system are reduced, the natural tendency of the system is to improve and optimize its function, directing the system back toward normalcy, or homeostasis. In more conventional medical terms, this is one of the fundamental concepts of the allostatic model.80,82–85 In naturopathic thinking, this is the removal of the obstacles to cure, which allows the emerging action of the vis medicatrix naturae, the vital force, the healing power of nature. This is the first step in the hierarchy of healing and what naturopathic physicians may call the overarching model in the clinical theory (the process of healing) of naturopathic medicine: the therapeutic order. This process can be seen in the naturopathic model of healing in Fig. 2.1. 

THERAPEUTIC ORDER AND NATUROPATHIC ASSESSMENT The Assessment Order: Components of a Vitalistic Assessment of Illness, Healing, and Health One thing I have learned in TCM, is that the assessment part implies the treatment, because the treatment is to balance what is imbalanced. Christy Lee Engel ND, Lac, Bastyr University, 2014 The assessment order is a set of prioritized components of a vitalistic naturopathic assessment of the patient based on, or dictated by observations of the • nature, • locus, or • center of gravity of the degenerative (disease) process. This degenerative disease process is evaluated in the context of natural health and healing systems, which interconnect • mind, body, and spirit; • the natural, cultural, and socioeconomic environments; • our heredity, and • how we live. These components have been recognized from ancient times through the present.86 Inclusive of conventional pathological evaluation, the naturopathic assessment order is a guideline to identifying and assessing various types, levels of, and priorities in the underlying causation of degenerative and dysfunctional conditions. The assessment order provides an ordered, nonrigid, dynamic framework (leading to the therapeutic order) for gauging the “center of gravity” of the disease process (the most efficient level at which to intervene to engage the patient’s healing response). By carefully assessing the status of the patient’s health and vitality and identifying components currently contributing to the disease process, the underlying causes become evident. These components

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BOX 2.6  Naturopathic Medicine Determinants of Health, Factors That Influence Health Inborn Determinants Genetic makeup (genotype) Intrauterine/congenital factors Intrauterine influences: maternal nutrition, health, and lifestyle Maternal exposures: drugs, toxins, illnesses, viruses, psycho-emotional Constitution: determines susceptibility  Disturbances/Disturbing Factors Illnesses: Patho-biography Medical interventions (or lack of) Physical and emotional exposures, stresses and trauma Toxic and harmful substances Trauma (physical/emotional) Toxemia Addictions Environmental disturbances, stress: environmental, physical, emotional  How We Live—Hygienic, Lifestyle, Psycho-emotional, Spiritual, Socioeconomic, and Environmental Factors Spirit Spiritual life/practice Self-assessment Relationship to larger universe (trust, consciousness, compassion)  Exposure to Nature/Environment Fresh air Clean water

Natural light Geography and ecosystem Exposure to natural systems, wild places, cycles  Diet, Nutrition, and Digestion Unadulterated food Optimal nutrition  Rest and Exercise Rest and sleep Recreation Exercise and movement Breath Vital force, vital reserve, energy Structural integrity  Socioeconomic Factors Loving and being loved Meaningful work Culture Community Government/public policy Environment Income and economic Health care (quality and access) Education

From Snider P, Zeff J, Myers S, DeGrandpre Z, et al. Course syllabus: NM5114, Naturopathic Clinical Theory. Seattle, WA: Bastyr University; 1997–2012.

BOX 2.7  Scientific Considerations:

Subclinical Inflammation and Chronic Illness It is becoming increasingly evident that many chronic diseases may have a long subclinical phase, most involving the inflammatory process. As mentioned, a chronic, subclinical inflammatory state has been linked to a number of disorders, including insulin resistance,152 obesity,153 vascular disease,154–157 hypertension,158 and aging.159

BOX 2.8  Scientific Considerations:

Determinants of Health Within Public and Community Health Concerns There exists an increasing consensus that Crohn’s disease and ulcerative colitis result from the combined effects of four important factors, none of which is individually sufficient to cause the disease. These four factors are the global changes in the environment, alterations in the microbiome of the intestine, multiple genetic factors, and aberrations or maladaptations in both the innate and adaptive immune systems.160–163 These four factors, considered to be vital to the development and the increased rates of irritable bowel disease, are quite similar to the determinants of health described in Box 2.6. This serves as a further example of the growing appreciation for the similarities (with important differences) between naturopathic medicine and public and community health.

are assessed for presence, absence, onset, triggers, depth, duration, and modalities and for physiological, psychospiritual, mental, biofield, organ system, and tissue targets. Components to be assessed include (1) determinants of health; (2) vitality; psychospiritual, mental, and energetic availability; and vital force; (3) physiological

and energetic systems; (4) structure and musculoskeletal components; (5) the pathology itself, its biochemistry, histology, and pathophysiology; and (6 and 7) the level and strength of specific, targeted, managerial, and higher-force interventions necessary for patient safety and reduction of suffering. Using the assessment order also engages the power of the patient– physician relationship: docere. “If the whole reason for the assessment is to develop a treatment plan [suitable to the patient’s safety and health recovery], that is one way to look at it. When we add the docere experience between physician and patient, then we add the complexity of the two systems, the intention of the physician, the energetic of the Vis—and we have a whole new dynamic in the assessment process, which itself begins to be the treatment process,” notes Christy Lee Engel ND, LAc. The case-taking and evaluation process thus begins the treatment process. It is the foundation of the doctor–patient relationship. Subjective and objective data contribute to both the pathological and the vitalistic assessment. The pathological assessment is viewed as partial although valuable information within the context of the entire vitalistic naturopathic assessment. The naturopathic assessment, in effect, places the disease process, its specific pathophysiology, and its staging within the broader context of the patient’s vitality, constitution, etiologic factors (never been well since), and underlying or root causes and leads to the level of intervention suggested by the therapeutic order. The patient’s story or patho-biography (Box 2.9) is an essential and powerful tool for making a complete naturopathic assessment. All information, subjective and objective (S, O), leads to the diagnosis and naturopathic assessment summary using the naturopathic assessment order (A) and to the treatment plan using the naturopathic therapeutic order (P). 

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The Naturopathic Medicine Assessment Order Components of a vitalistic assessment of illness, healing, and health I.  Evaluate Conditions for Health—Assess Naturopathic Medicine Determinants of Health Identify/assess inborn and constitutional factors (innate vitality and susceptibility)—genetics, epigenetics, constitution, elements, and individual perceptions and values. Identify/assess disturbing factors (obstacles to healing)—behavioral, hygienic, socioeconomic, environmental, psycho-spiritual, and cultural determinants. Identify/assess health-promoting factors—behavioral, hygienic, socioeconomic, environmental, psycho-spiritual, and cultural determinants.  II. Evaluate Vis Medicatrix Naturae: The Healing Power and Processes of Nature Assess vital force, vitality, energetic/biofield, and stage and status of healing/illness processes. Assess vital reserve and vitality. Assess spiritual state. Assess awareness, energy, and biofield. Assess vital force, direction, and intensity in healing versus illness process simillimum, signature, dual effect, chronobiology, minimum dose suppression, return of old symptoms/retracing Hering’s rules—direction of symptom progression Felt sense by patient of trust, energy, awareness, ability to love Assess impact of intention, healing practices, and healing interaction on healing response. Assess healing response—strength, direction, response versus reaction or crisis.  III.  Conduct a Functional Assessment of Physiological and Bioenergetic Systems Assess disturbances in physiological, energetic, and organ and cellular system functions and interrelationships—over-/underactivity, burden, obstruction, disorder, nourishment. Examples include neuroendocrine, digestive, emunctories, psycho-spiritual, and so forth.  IV.  Evaluate Structural Obstacles to Health Assess musculoskeletal and structural integrity. Assess need for nutrients, movement, and exercise to support musculoskeletal integrity.  V.  Conduct Pathological Assessment Assess symptoms, urgency, suffering, and potential for damage.  VI.  Assess Need, Risks, and Benefits of Highest-Force Interventions Patho-biography, follow-up, physical examination, signs, symptoms, lab imaging Copyright 2015. All Rights Reserved. Snider P, Zeff J, Pizzorno J, Myers, S, Sensenig J, Newman Turner R, Warren D, Kruzel T. Naturopathic Medicine Assessment and Therapeutic Order: The Naturopathic Medicine Assessment Order. The Foundations of Naturopathic Medicine—The Healing Power of Nature. The Holly Retreat 2015. Snoqualmie, WA: Foundations of Naturopathic Medicine Institute and Foundations of Naturopathic Medicine Project. http://www.foundationsproject.com. http://www.fnminstitute.org.

BOX 2.9  The Pathobiography In spite of the organic roots of our medical genesis, any [physician] must [not ] consider... illness purely as a material process of organic alteration. The integration of this illness in its anatomo-clinical aspect in the patient as a person enables us to discover the morbid dynamics underlying the pathological process. The “patho-biographic” case history assumes particular interest as it involves the entire psychic, emotional, affective life of the patient, his cravings, frustrations, achievements, anxiety to succeed, his perspectives. His patho-biographic past is no more than the process of psycho-physical adaptation of the individual to his circumstances and where physiopathological alterations are no more than the objective expression and the ultimate result of such adaptation.” Used with the permission of Dr. Eugenio Candegabe, Journal of the Society of Homoeopaths.

THERAPEUTIC ORDER The naturopathic medicine therapeutic order is a natural hierarchy of therapeutic intervention based on or dictated by observations of the nature of the healing process from ancient times through the present.86 The therapeutic order is a systematic approach to engaging the patient’s healing response by working with the order of effective

intervention inherent in the healing power and processes of nature. This order is simultaneously linear, holarchical, and recursive and functions as a multilayered, complex system powered by the vital force. It is either limited or increased in its efficiency by the level of the patient’s vitality. By removing obstacles to healing, establishing health-promoting factors (giving the body and spirit what it needs), and stimulating the vital force, vitality is increased, igniting the orderly self-healing processes of vis medicatrix naturae. Naturopathic physicians have long recognized (Box 2.10) that (1) the healing process is observable—a natural phenomenon (law of nature) seen consistently in health, healing, and illness (e.g., similar to laws of biology, physics, and regularities of other natural sciences); (2) “Naturopathic medicine recognizes this healing process to be ordered and intelligent” (Snider and Zeff et al., AANP House of Delegates, 1989, 2001, 2011). The principle vis medicatrix naturae guides the physician to ignite this ordered process by removing obstacles to healing (disturbing factors) and establishing a healthy internal and external environment (AANP 1989). This is accomplished by establishing individualized global health determinants that “treat disease by restoring health.” Less detailed therapeutic orders also exist in traditional Chinese, Tibetan, Ayurvedic, and Unani medicine theories. The therapeutic order is a natural ordering of the modalities of naturopathic medicine and their application. The concept is somewhat

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A Hierarchy of Healing: The Therapeutic Order

BOX 2.10  Nature’s Healing Order—Lindlahr Lindlahr referred to the vis medicatrix naturae as “the constructive principle in nature.” In 1914 he described the healing order this way: “The underlying causes of disease must be removed before we can cure chronic disease and bring about a normal condition of the organism…” the true healer is … the vis medicatrix nature which ... endeavors to repair, to heal and to restore all that the physician can do is to remove obstructions and to establish normal conditions within and around the patient, so that the healer within can do his work to the best advantage. . . . Though we cannot heal and give life, we can in many ways assist the healer within. We can teach and explain Nature’s Laws, we can remove obstructions and we can make the conditions within and around the patient more favorable for the action of Nature’s healing forces.” Lindlahr, H. Nature Cure. http://www.fulltextarchive.com/pdfs/ Nature-Cure.pdf. Nature Cure. 1913; 460, 532.

BOX 2.11  The Therapeutic Order: Hierarchy

of Healing

1. Establish the conditions for health. Identify and remove disturbing factors. Institute a more healthful regimen. 2.  Stimulate the healing power of nature (vis medicatrix naturae): the self-healing processes. 3. Address weakened or damaged systems or organs. Strengthen the immune system. Decrease toxicity. Normalize inflammatory function. Optimize metabolic function. Balance regulatory systems. Enhance regeneration. Harmonize with your life force.2 4. Correct structural integrity. 5. Address pathology: Use specific natural substances, modalities, or interventions. 6. Address pathology: Use specific pharmacological or synthetic substances. 7. Suppress or surgically remove pathology. The actual therapeutic order may change, depending on the individual patient’s needs for safe and effective care. The needs of the patient are primary in determining the appropriate approach to therapy. Acute and chronic concerns are both addressed using the therapeutic order.91 Acute concerns are addressed first to avoid further damage, risk, or harm to the patient. The point of entry for assessment and therapy is dependent on each patient’s need for effective and safe care, healing, and prevention of suffering or degeneration.2,91 From Zeff J, Snider P. Course syllabus: NM5131, Naturopathic clinical theory. Seattle, WA: Bastyr University; 1997–2005.

plastic, in that one must evaluate the unique needs, and even the unique healing requirements, of the specific patient or situation.87 However, the nature of healing dictates a general approach to treatment. In general, this order is listed in Box 2.11. An analogy for the therapeutic order in Australian integrative medicine is what is called the “softer option” model of patient care.88 This model recognizes that, given a choice, the patient will generally choose the softer option, provided that this does not limit a harder option if the softer option fails. By way of example, given a choice between an antibiotic and amputation for a minor cut finger, most people would choose the softer option. Expanding this range of choice to an herbal cream, antiseptic (herbal or nonherbal), and a Band-Aid; an antibiotic; or amputation, we develop a therapeutic order ranging from the

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softest option (the least force) to the hardest option (the higher-force intervention). The therapeutic order can be seen as a progression of therapeutic interventions that begins with this “softer option.”

Acute and Chronic Concerns As discussed previously, there is an inherent drive toward health that is observable within the patterns and processes of nature. The drive is not perfect. There are times when, unguided, unassisted, or unstopped, the drive goes astray, causing preventable harm or even death in patients; the constructive healing intention89 becomes destructive pathology. The ND is trained to know, respect, and work with this drive in both acute and chronic illness, using the therapeutic order, and to know when to wait or do nothing, act preventively, assist, amplify, palliate, intervene, manipulate, control, or even suppress using the principle of the least force.90 Acute and chronic concerns are both addressed and managed using the therapeutic order.91 Acute concerns are addressed first to avoid further damage, risk, or harm to the patient. The point of entry for assessment and therapy is dependent on each patient’s need for effective and safe care, healing, and prevention of suffering and degeneration.70,91 Naturopathic physicians avoid suppression of symptoms in acute circumstances unless necessary for patients’ well-being and safety. Instead, wherever possible, therapies for acute concerns use the least force (minimizing toxic side effects, suppression of natural functions, and physiological burdens) available to intervene effectively, healing or palliating as needed. The full range of modalities, from nutrition to homeopathy, botanical and physical medicine, hydrotherapy, counseling, prescriptive medication, and surgery, is available to the patient as the naturopathic physician works to apply the least force in providing effective preventive, acute, and chronic care.91 

Establish the Conditions for Health

Identify and Remove Disturbing Factors If one understands health to be the natural state and “disturbance” the original culprit, then identifying and reducing disturbance is the obvious first step, unless there is immediate danger to life or limb, in which case acting to reduce suffering and preserve life or limb is paramount. In most chronic disease, neither is immediately threatened. This understanding dictates the primary treatment goal the physician must attend to: the identification and amelioration of those factors disturbing health, especially factors that most disturb health (inappropriate diet, excessive stress, and spiritual disharmony). To understand what disturbs health, one must understand what determines health. The naturopathic physician evaluates a patient with reference to the determinants of health to discover wherein the patient’s health is disturbed. In this step, the physician is essentially removing the obstacles to cure and allowing the vis medicatrix naturae to do its work. Among these many possibilities, the most significant are attitude, diet, digestion, psychological and other stressors, and what might be called “spiritual integrity.” Humans have a transpersonal dimension and can be seen as spiritual beings. Spiritual here is not defined by religion or belief in a deity or deities; it is that component of individuals that gives rise to their inner compass, their “joie de vivre” and their internal meaning of life, their core beliefs, and their values. Perceived in this way, it can be seen that many people in society are experiencing “spiritual crises.”92 Although the general purview of the physician is the body, that instrument cannot be separated from the spirit that animates it. If the spirit is disturbed, the body cannot be fundamentally healthy. Hahnemann, the brilliant and insightful founder of homeopathy, instructed physicians to attend to the spirit.93 Disturbance in the spirit permeates the body and eventuates physical manifestation. Physicians are responsible

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BOX 2.12  Scientific Considerations:

Toxemia Today

Using conventional medical terminology, disorders derived from environmental, dietary, and lifestyle factors are termed idiopathic environmental intolerances, multiple chemical sensitivities,98,164–166 or sometimes oxidative stress disorders.167–171 The terminology may be different, but each term describes the same symptomatology. Environmental toxins accumulate, and chronic inflammation increases. These exogenous and endogenous toxins and the lack of exercise stress the system further. The ketogenic diet to control epilepsy may be considered one example of the successful application of diet to control symptoms.172

for perceiving such disturbances and addressing them. At colleges of naturopathic medicine in Australia, the United Kingdom, and North America, faculty work with naturopathic medicine students to develop their ability to perceive the spiritual nature of an individual as a foundational skill in addressing the spiritual crises or fundamental needs that have a profound effect on health and well-being. Using this definition, both atheists and agnostics can be seen to have a spiritual aspect. This definition also removes spirituality from religiosity in a way that does not denigrate any individual religious belief, allowing the naturopathic clinician to explore this aspect as part of routine care. One of the oldest concepts in naturopathic medicine is the concept of toxemia. Toxemia is the generation and accumulation of metabolic wastes and exogenous toxins within the body. These toxins may be the results of maldigestive processes, intermediate metabolites, environmental xenobiotics, and colon bacterial metabolites, for example. These toxins become irritants within the body, resulting in the inflammation of tissues and the ultimate interference with normal biochemical processes.94 The maldigestive and dysbiotic95,96 origin of these internally and externally derived toxins is the result of an inappropriate diet, broad-spectrum antibiotics, and the effects of excessive stress on digestion.97 Eating a diet that cannot be easily digested or that is out of appropriate nutrient balance for the individual results in the creation of metabolic toxins in the intestines.95–98 Stress, causing the excessive secretion of cortisol and adrenaline, results in the decrease of blood flow to the digestive process, among other effects,80,82–85 which decreases the efficient functioning of digestion and increases the tendency toward maldigestion, dysbiosis, and toxemia. Physicians can now easily measure the degree of toxemia in various ways (urinary indican or phenol98). The older concept of toxemia,99,100 with scientific advances in its understanding91,99 (Box 2.12), may now be productively combined with an understanding of the newer concept of allostasis82–85 and the historical89,100 and reemerging discussion on the inflammatory component of many, if not most, chronic diseases. Spiritual disharmony, inappropriate diet, digestive disturbance, stress, and toxemia (leading to inflammation) are considered primary causes of chronic illness and must be addressed if healing is to occur. Beyond these, other disturbing factors must be discerned and addressed, whichever pertain to the individual patient.101,152–154,158,159,165–171 

Institute a Healthier Regimen As a corollary of the first step, once physicians have determined major contributing factors to illness, they construct a healthier regimen for the patient. Some disturbing factors can be eliminated, like inappropriate dietary elements.110,111 Others are a matter of different choices or living differently. The basics to consider are appropriate diet, appropriate rest and exercise, stress moderation, a healthy environment, and a sense of spiritual fulfillment.82,92,141,142,145,146,148

If this model is correct, these measures alone should result in enhanced health. The problem arises in knowing how to do these things. What is an appropriate diet? This is an area of considerable controversy. Physicians think about diet in many different ways. The goal of dietary improvement is to reduce the symptomatic consequences of the patient’s diet and provide optimal nutrition to the patient. The point here, regardless of how this is done, is that it is central and essential for fundamental health improvement. If the diet is not correct, if digestion is not appropriate, if nutrition is not adequate, the patient cannot appropriately function or improve, and the scene is potentially set for chronic inflammatory conditions and the resetting of the adaptive allostatic and homeostatic set points. If the diet and digestion are appropriate, the basis for improvement in other areas is enhanced. The same is true with these other fundamental elements, to which Lindlahr referred in the first element of his catechism, “return to nature”: exercise, rest, dress, and so forth.29 These have been expanded in the “determinants of health.” They create the basis for improvement. What this really means is to change the “terrain,” the conditions in which the disease has formed—not only to change but to improve the conditions so that there is less basis for the disease. Hahnemann addresses this on the first page of his Organon of Medicine.93 He identified four tasks for the physician: to understand the true nature of illness, “what is to be cured”; to understand the healing potential of medicines (whether they enhance or suppress function); to understand obstacles to recovery and how to remove them (the determinants of health); and to understand the elements that derange health and how to correct them so that recovery may be permanent.93 Changing and improving the terrain in which the disease developed is the obvious first step in bringing about improvement. This sets up the basis for the following elements to have the most beneficial effects. 

Stimulate the Self-Healing Mechanisms A certain percentage of patients will improve sufficiently simply by removing disturbing factors and establishing a healthier regimen. Most require more work. Once the patient is prepared, once the terrain is beginning to clear of disturbing factors, then one begins to apply stimulation to the self-healing mechanisms. The basis of this approach is the underlying recognition of the vis medicatrix naturae, the tendency of the body to be self-healing, the wisdom and intelligence within the system that constantly tends toward the healthiest expression of function, and the healing “forces” in the natural environment (air, water, light, etc.). The body heals itself. The physician can help create the circumstances to promote this. Then, as necessary, the physician stimulates the system. This also requires that attention be given to the patient’s emotional state of mind because the psychological condition of the patient is often of major importance.113,114 One of the best ways to do this is through constitutional hydrotherapy, as developed by Otis G. Carroll, ND, early in the past century. This procedure is simple, involving the placement of hot and then cold towels on the trunk and back, in a specific sequence (depending on the patient), usually accompanied by a sine-wave stimulation of the digestive tract. This is a dynamic treatment, simple, inexpensive, and universally applicable. It helps recover digestive function, stimulates toxin elimination, “cleanses the blood,” enhances immune function, and has several other effects. It moves the system along toward a healthier state.115 Exercise often achieves similar results. Many naturopathic modalities can be used to stimulate the overall vital force. More specific approaches to stimulation, although general in effect, are applied differently to each patient and have a less general effect than those previously mentioned. Homeopathy and acupuncture116–118 are often the primary methods of such stimulation. They add little to the system; they are not gross chemical treatments. They work with what is there, stimulating a reaction, stimulating function, and correcting disturbed patterns.

CHAPTER 2 

A Hierarchy of Healing: The Therapeutic Order

Each method helps move the system out of its disturbed state and, with the reduction of encumbrance, helps move it toward health. Finally, exposure to the patterns, rhythms, and forces of nature is a traditional part of naturopathic medicine and the tradition of nature doctors throughout the world. As previously noted, “We exist as part of complex patterns of matter, energy, and spirit,”2 and the natural progression of these patterns, and the drive toward health inherent in them, is a natural ally for the physician. Exposure to appropriate rhythms, patterns, and forces of nature strengthens vitality and stimulates the healing power of nature. 

Support Weakened or Damaged Systems or Organs Some systems or functions require more than stimulation to improve. Some organs are weakened or damaged (e.g., adrenal fatigue after prolonged stress), and some systems are blocked or congested (e.g., the hepatic detoxification pathways) and require extra help. This is where naturopathic physicians use their vast natural medicinary. Botanical medicines can affect any system or organ, enhancing its function, improving its circulation, providing specific nutrition, and stimulating repair. Glandular substances can be applied to a similar purpose. Plus, there are a growing number of evidence-based “nutraceuticals”— biological compounds that enhance metabolic pathways and provide specific substances to enhance metabolic function.119–130 Naturopathic physicians can also apply specific homeopathic medications, usually in the lower potencies, which act nutritively and can stimulate specific organs or functions. This method, generally referred to as drainage, can be used to stimulate detoxification of specific substances from the body in general or of specific organ systems or tissues. Dr. Pizzorno’s work in Total Wellness and The Toxin Solution131,132; the work of “functional medicine” leader Jeffrey Bland, PhD; and the Textbook of Functional Medicine by Jones90 exemplify the clinical strategies applied at this level of the therapeutic order. These strategies are used to restore optimal function to an entire physiological system (immune, cardiovascular, detoxification, life force, endocrine).131,132 One can also use specific exercises to stimulate or enhance organ health. Some systems of yoga and qi gong are organ specific. Specific applications of hydrotherapy and other physiotherapy systems can be applied to enhance the function of organs or tissues. It has been the clinical experience of many naturopathic physicians that these methods, combined with an appropriate diet and a healthier regimen, along with constitutional hydrotherapy, appropriate homeopathy, and acupuncture, bring most health problems back to normal, without negative consequence, rapidly, efficiently, and permanently. 

Address Structural Integrity Many structural problems result from generalized stress of some kind on internal systems. For example, midback misalignment or discomfort (T1–T12) is often found associated with a history of underlying stress on the digestive organs, the enervation of which originates at those spinal segments. One can manipulate the vertebra back into proper alignment or massage contracted musculature, but until one corrects the underlying functional disturbance, there will be a tendency to repeated structural misalignment. In some circumstances, the singular problem may be simply structural disintegrity. One may have fallen or been hit in some fashion and simply needs the neck manipulated back into proper alignment and the surrounding soft tissue relaxed. There may be no dietary error or other disturbance aside from the original injury, and correction requires only simple manipulation or therapeutic massage. This is an example of the flexibility of the therapeutic order concept. In this case, first-order therapeutics manipulate the cervical spine or relax chronically contracted muscles. Usually,

23

however, the problem of structure is part of the larger problem, and such intervention becomes a fourth-order therapeutic.70 Reintegrating structure can occur in many ways, one of which is the method of “bone cracking” known to the ancient Greeks and Chinese and probably all other ancient healing cultures. However, there are nonforce manipulative systems that include many modalities of therapeutic massage. Some systems of exercise are designed to reintegrate and maintain normal structural relationships. Any of these might be appropriate to a specific patient. By approaching the problem in the context of the therapeutic order, one can expect structural corrections to be required only occasionally and for the results to be more or less permanent. 

Address Pathology: Use Specific Natural Substances, Modalities, or Interventions Having gone through the first four steps of this therapeutic hierarchy, most patients improve. The improvement is based on the sound footing of the underlying correction or removal of fundamental causative elements. It is also based on the intrinsic nature of the body to heal itself using the least possible force. Most pathology improves or disappears under these circumstances, but sometimes it is necessary to address pathology. This may be the case because the particular pathology may be threatening to life or limb. Acting on this threat is imperative. It can often be done with naturopathic means, directed specifically against the pathology. Biochemical or genetic individuality also can demand an emphasis at this level of intervention. One of the major conflicts in naturopathic medicine is that some practitioners find it expedient to diagnose and treat pathology (the standard medical model) rather than pursue a naturopathic model of practice. This approach tends to be less satisfying and less productive of the most elegant outcomes and the long-term continued health of the patient. It also reduces the capacity of the physician to treat, such as in cases where there is no evidence-based treatment for the pathology in question, or where there is no clear diagnosis (i.e., no distinct pathology to treat). This approach is increasingly referred to as “green allopathy.” However, the vast body of knowledge that naturopathic education presents in this arena makes such an approach seductive, especially in a culture that more or less expects, supports, reinforces, and pays for a biomedical (“allopathic”) approach to diagnosis and treatment. It is easy to do this. The culture is accustomed to this model and often expects to encounter this in the naturopathic physician’s office. In some states, such as Oregon, Washington, and Arizona, where the naturopathic formulary includes most antibiotics and many pharmaceutical drugs, one can practice almost without distinction from a medical doctor. The typical naturopathic formulary is often sufficient to prescribe on a strictly pathological basis. The problem with this is that it is generally not as effective, especially in the treatment of chronic disease. The value of naturopathic medicine in our culture is not that naturopathic physicians can function almost like medical doctors, with a “natural” formulary instead of drugs. It is that they offer a fundamentally different approach, one based on the restoration of health rather than the treatment of disease. Given all of this, it still may be useful to directly address the pathological entity or its etiology.112,133-136 When treating an antibioticresistant infection, for example, it may be useful to apply botanical medicines with specific antibiotic properties, along with immune tonics and the more fundamental steps of this therapeutic hierarchy. In difficult cases, such as many cancers, using agents that have specific, pathology-based therapeutics may be an essential element of comprehensive treatment. The naturopathic formulary provides a vast and increasing number of such options. One advantage of such treatment

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Philosophy of Natural Medicine

is that, in general, when applied by a knowledgeable practitioner, it rarely adds more burden or toxicity to the system. Naturopathic pathology-based treatments still follow the dictum “do no harm.” 

generally avoid suppression, which is a primary way in which physicians can inflict harm, even with the best of intentions. 

Address Pathology: Use Specific Pharmacological or Synthetic Substances

THEORY IN NATUROPATHIC MEDICINE

About 800,000 medical doctors and osteopathic physicians in the United States are trained in the science of pathology-based treatment, using pharmaceuticals and surgery, for example. There are times when such an approach is necessary to preserve life, limb, or function. Although some naturopathic physicians, by training and by statute, may prescribe pharmaceuticals or perform minor office procedures and surgeries, naturopathic physicians may also refer patients in need of such services to appropriate standard medical doctors (MDs) or medically trained osteopaths (DOs). In a growing number of states, NDs can legally provide an expanding range of prescription drugs. Although this is an important tool for the naturopathic primary caregiver, this privilege requires enhanced responsibility for the ND to prescribe those substances only as needed—and to thoroughly rely on applying the least force appropriate to effect recovery and protect patient safety. Both Dr. Lust (at the end of his life) and Dr. Bastyr recognized the need for NDs to have the ability to access, as needed, prescriptive medications and perform minor office procedures to function as primary caregivers. However, both admonished that the philosophy and principles of the medicine guide their judicious use—only as truly needed, based on the least force necessary to restore the patient to health. Naturopathic physicians are well trained in this regard and respect the necessity and utility of standard medical practice in appropriate situations. Some disagreement exists regarding which situations may be appropriate. The AANP has developed position papers to resolve some of these questions. In general, although recognizing the necessity of such treatment, most naturopathic physicians also recognize that such treatment often carries consequences that also must be addressed. 

Suppress Pathology Sometimes it is necessary, when there is a risk of harm to the patient’s health or tissue or to relieve suffering, to suppress pathology. Medical doctors are especially trained in this art and have powerful and effective tools with which to do this. Unfortunately, suppression, because it does not fundamentally remove or address essential causative factors (e.g., dietary error) often results in the development of other, often deeper disturbance or pathology. Because much pathological expression is the result of the actual self-healing mechanisms (e.g., inflammation), suppressive measures, in general, work in opposition to the vis medicatrix naturae. The result of suppression is that the fundamental disturbing factors are still at play within the person, still disrupting function to some extent, whereas the suppression reduces the symptomatic expression and resolution of disturbance. One simple example of this is the overuse of oral corticosteroidal anti-inflammatory and antihistaminic drugs in the treatment of acute asthma. This usually effectively opens the airways. However, prolonged use weakens the patient. If the treatment persists, the patient may become immune compromised or osteoporotic or can develop psychological disorders. These symptoms are part of the long-term effects of steroids.137 It may, of necessity, maintain breathing, but the long-term cost to the organism can be high. Suppression, although it may be lifesaving, often has serious consequences. With standard medical methods of care, the cure of chronic illness is often elusive. This is the benefit of the naturopathic approach: by taking a nonsuppressive course of action, based on sound physiological principles, one can often restore health without recourse to the potential damage of suppression. Naturopathic physicians, although recognizing the occasional necessity of suppressive approaches,

The therapeutic hierarchy is based on the observation of the nature of healing and the inherent order of the healing process. It is part of a unifying theory of naturopathic medicine, an outgrowth of the principles that underlie naturopathic thinking. It provides the physician with instructions that order the many therapeutic modalities used by the practice. The consensus definition of naturopathic medicine, adopted by the AANP in 1989, is a statement of identity, distinguishing naturopathic medicine from other systems of medical thought. Contained within it is a set of instructions regarding the practice of the medicine. The three concepts discussed here—“disease as process,” “the determinants of health,” and “the therapeutic order”—are an articulation of these instructions. They are presented as a clinical theory of naturopathic medicine. They have been crystallized, as is the definition, from the observation by nature doctors throughout time and across many traditions of the nature of health, disease, and healing. They provide the physician with instructions. These instructions include a procedure for thinking about human illness in such a way that one can approach its cure in an ordered fashion by understanding its process as an expression of the vis medicatrix naturae. It provides the framework for truly evaluating the patient as a whole being: spiritual, mental/emotional, and physical, rather than as a category of pathology. Plus, the theory of naturopathic medicine provides the physician a system for organizing and efficiently integrating the vast therapeutic array provided in naturopathic medicine. Ultimately, it satisfies Hahnemann’s observation of the ideal role of medicine, that “the highest ideal of cure is rapid, gentle and permanent restoration of the health … in the shortest, most reliable and most harmless way, upon easily comprehensible principles.”93 The roots of the observations that form this theory are traceable through the mid- and early 20th century, to the traditional theory of the 19th-century European nature cure, and to the roots and theories of traditional world medicines. Hippocrates’s writings on the vis medicatrix naturae form a foundation that historically underpins the development of this theory.138,139 Finally, it is observable across many traditional world medicines that various healing orders are described. Such structures hold implications for public and community health priorities and suggest the reprioritization of healthcare priorities and financing. Implications for public policy and the growing national disease debt invite exploration. Although this presentation is not comprehensive, the attempt has been made to demonstrate these roots, at least in some of their major articulations. The work presented here is a continuation of this historical process, which ultimately is driven by the true mission of the physician: to ease suffering and to preserve life. What Methods of Cure Are in Conformity with the Constructive Principle in Nature? Those methods which: Establish normal surroundings and natural habits of life in accord with Nature’s Laws. Economize vital force. Build up the blood on a natural basis, that is, supply the blood with its natural constituents in right proportions. Promote the elimination of waste matter and poisons without in any way injuring the human body. Arouse the individual in the highest possible degree to the consciousness of personal accountability and the necessity of intelligent personal effort and self-help.29

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1.  See Chapter 5 for a more comprehensive and more fully documented— with some differences—history of naturopathic medicine. 2. Pizzorno J, Snider P. Naturopathic medicine. In: Micozzi MS, ed. The Fundamentals of Complementary and Alternative Medicine. New York: Churchill Livingstone; multiple editions. 3. Cody G. The history of naturopathic medicine. In: Pizzorno J, Murray M, eds. Textbook of Natural Medicine. New York: Churchill Livingstone; 1999. 4. Kirchfeld F, Boyle W. The Nature Doctors: Pioneers in Naturopathic Medicine. Portland, OR: Medicina Biologica; 1994. 5. Schramm A, ed. Yearbook of the International Society of Naturopathic Physicians and Emerson University Research Council. Los Angeles: International Society of Naturopathic Physicians; 1945. 6. Tribe W. Personal communication. National College Professional Survey. Portland, OR: National College of Naturopathic Medicine; 2008. 7. Wendel P. Standardized Naturopathy. Brooklyn, NY: Paul Wendel; 1951. 8. Kirchfeld F, Boyle W. Nature Doctors. East Palestine, OH: Buckeye Naturopathic Press; 1994. 9. Freibott G. Report Submitted to Lanso Cavasos, Secretary of Education. Washington, DC: U.S. Department of Education; 1990. 10. Spitler HR. Basic Naturopathy, a Textbook. New York: American Naturopathic Association; 1948. 11. Wendel P. Standardized Naturopathy. Brooklyn, NY: Paul Wendel; 1951. 12. Coulter H. Divided Legacy: A History of the Schism in Medical Thought. Washington, DC: Weehawken Book Company; 1973. 13. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129–136. 14. Lear L. Rachel Carson Biography. http://www.wilderness.net/index .cfm?fuse=feature0407. Accessed August 10, 2011. 15. Enrollment records. National College of Naturopathic Medicine. Accessed June 20, 2004. 16. Kirchfeld F, Boyle W. The Nature Doctors: Pioneers in Naturopathic Medicine. Portland, OR: Medicina Biologica; 1994. 17. Snider P. The future of naturopathic medical education—primary care integrative natural medicine: the healing power of nature. In: Cronin M, ed. Best of Naturopathic Medicine: Anthology 1996: Celebrating 100 Years of Naturopathic Medicine. Tempe, AZ: Southwest College of Naturopathic Medicine Publications; 1996. 18. Snider P. Integration project survey results: report to the AANMC dean’s council [Database]; 1999. 19. Standish L, Calabrese C, Snider P, et al. Naturopathic medical research agenda: report to NCCAM: Draft. 2004:5. 20. Tilden JH. Toxemia Explained: An Antidote to Fear, Frenzy, and the Popular Mad Chasing After So-Called Cures: The True Interpretation of the Cause of Disease, How to Cure Is an Obvious Sequence. Rev. ed. Denver: FJ Wolf; 1926. 21. Trall R. The True Healing Art. New York: Fowler & Wells; 1880. 22. Graham S. Greatest Health Discovery: Natural Hygiene & Its Evolution Past, Present & Future. Chicago: Natural Hygiene Press; 1860. 23. Kellogg J. Rational Hydrotherapy. 2nd ed. Philadelphia: FA Davis Co; 1903. 24. Kuhne L, Lust B. Neo-Naturopathy: The New Science of Healing or the Doctrine of the Unity of Diseases. Butler, NJ; 1917. 25. Kuhne L, Lust B. The Science of Facial Expression: The New System of Diagnosis, Based on Original Researches and Discoveries. Butler, NJ; 1917. 26. McFadden B. MacFadden’s Encyclopedia of Physical Culture. Vol. 5. New York: Physical Culture Publishing; 1920. 27. Rikli A. Die Grundlerhren der Naturheilkunde einschliesslich “Dia atmospharische Kure,” “Es werde Licht” und “Abschiedsworte” [The Fundamental Doctrines of Nature Cure including “the Atmospheric Cure,” “Let There Be Light” and “Words of Farewell”]. 9th ed. Wolfsburg, Germany: G. Rikli; 1911. 28. Tilden JH. Impaired Health: Its Cause and Cure—A Repudiation of the Conventional Treatment of Disease. 2nd ed. Denver: Tilden; 1921. 29. Lindlahr H. Nature Cure: Philosophy and Practice Based on the Unity of Disease and Cure. Chicago: Nature Cure Publishing; 1913.

30. Kneipp S. Thus Shalt Thou Live. Kempten, Bavaria: Koesel; 1889. 31. Kneipp S. My Water Cure. UK: Thorsons; 1979 (reprint of 1891 edition). 32. Kneipp S. My Will. Kempten, Bavaria: Koesel; 1894. 33. Trall RT. Hydropathic Encyclopedia: A System of Hydropathy and Hygiene. New York: Fowlers & Wells; 1851. 34. Rausse JH. Der Geist der Graffenberger Wasserkur. Zeitz: Schieferdecker; 1838. 35. Rikli A. Die Thermodiatetik oder das tagliche thermoelectrische Licht und Luftbad in Verbindung mit naturfemasser Diat als zukunftige Heilmethode. Vienna: Braumueller; 1869. 36. Thomson S. A Brief Sketch of the Causes and Treatment of Disease. Boston: EG House; 1821. 37. Beach W. A Treatise on Anatomy, Physiology and Health. New York: W. Beach; 1847. 38. Ellingwood F. American Materia Medica, Therapeutics, and Pharmacognosy. Evanston: Ellingwood’s Therapeutist; 1919. 39. Felter H. The Eclectic Materia Medica, Pharmacology, and Therapeutics. Cincinnati: John K Scudder; 1922. 40. Boyle W. The Herb Doctors. East Palestine, OH: Buckeye Naturopathic Press; 1988. 41. Dictionary of Occupational Titles. Vol. 1. 3rd ed. Washington, DC: U.S. Department of Labor; 1965. 42. Schram A. Acts and laws. In: Yearbook of the International Society of Naturopathic Physicians & Emerson University Research Council. Los Angeles: International Society of Naturopathic Physicians; 1945. 43. Bradley R. Philosophy of naturopathic medicine. In: Pizzorno J, Murray M, eds. Textbook of Natural Medicine. New York: Churchill Livingstone; 1985. 44. AANP House of Delegates Resolution. Rippling River, OR; 1989. 45. Select Committee on the Definition of Naturopathic Medicine, Snider P, Zeff J, co-chairs. Definition of Naturopathic Medicine: AANP Position Paper. Rippling River, OR: AANP; 1989. 46. Select Committee on the Definition of Naturopathic Medicine. AANP 1987–1989. Report submitted to AANP in 1988, final recommendation submitted to AANP House of Delegates Rippling River, OR; 1989. 47. Snider P, Zeff J. Personal letters and communications, 1987–1989. 48. Zeff J. Convention theme: “what is a naturopathic physician?” AANP Q News. 1988;3(1):11. 49. Snider P, Zeff J. Definition of naturopathic medicine: first draft. AANP Q News. 1988;3:6–8. 50. North American Association of Naturopathic Medical Colleges Integration Project Survey 1997–1999. Preliminary report. October 26, 1999. Snider P, Zeff J, co-chairs. Mitchell M, Bastyr University Integration Project Student Task Force Chair. Monwai M, database and research assistant. 51. Snider P, Zeff J. Integration Project Report on Survey Data and Proposed Principles of Naturopathic Medicine to the AANMC Dean’s Council; 1999. 52. The integration project update 2000: AANP house of delegates principles survey, presented by Mitchell M, IP student task force chair 1997–2000. Comments presented by Snider S, Zeff J, co-chairs integration project 1996–2000. Monwai M, database manager. Saunders F, data analyst. 53. O’Keefe M, Milliman B, Zeff J. Proposed New Principles of Naturopathic Medicine: Wellness, Least Force, Relieve Suffering. Submitted to the AANP House of Delegates; 1996. 54. Resolution introduced in House of Delegates regarding new principles: passed 2000 AANP convention, Seattle, WA. The House of Delegates recommended that the discussion be moved to the academic community involved in clinical theory and practice for development. 55. Zeff J. The process of healing: a unifying theory of naturopathic medicine. J Naturopath Med. 1997;1:122–126. 56. Snider P, Zeff J, Sensenig J, et al. Towards a Unifying Theory of Naturopathic Medicine. AANP Plenary Session. Portland, OR: AANP; 1996. 57. Snider P. Integration project: timeline, scope of work, goals, methods. Proposal adopted by CNMC 1996, readopted by AANMC 1997–1998. 58. CNME report from Bastyr University. Standard XI and appendices: curriculum; 1999. 59. AANMC Dean’s Council minutes and correspondence; 2000. 60. Snider P, Downey C. Co-chairs. Invitation Letter, Supporting Information, Agenda, Minutes, Tools and Materials. AANMC Integration Project Retreat for Naturopathic Philosophy and Clinical Theory Faculty, Basic Sciences Chairs and Clinic Directors; 2001:20–21.

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FURTHER READINGS Festa A, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the insulin resistance atherosclerosis study (IRAS). Circulation. 2000;102(1):42–47.

Kiecolt-Glaser JK, McGuire L, Robles TF, et al. Emotions, morbidity, and mortality: New perspectives from psychoneuroimmunology. Ann Rev Psych. 2002;53:83–107. Shekelle PG, Adams AH, Chassin MR, et al. Spinal manipulation for low-back pain. Ann Int Med. 1992;117(7):590–598. Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Immunol Allergy Clin North Am. 2009;29(2):381–393. Yetley EA. Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr. 2007;85(1):S269–S276.

3 The History of Naturopathic Medicine: Origins and Overview George W. Cody, JD, MA, and Heidi Hascall*, MA

OUTLINE Introduction, 25 Brief History of Early American Medicine With an Emphasis on Natural Healing, 26 Medicine in America: 1800–1875, 26 The American Influence, 28 The Beginnings of “Scientific Medicine”, 30 The New “Sects”, 31 The Founding of Naturopathic Medicine, 31 Benedict Lust, 31 Introduction, 32 The Principles, Aim, and Program of the Nature Cure System, 33 Life Maltreated by Allopathy, 34

What Is Life?, 34 The Naturopaths, 34 The Program of Naturopathic Cure, 34 The Germanic Influence, 35 The Convergence With American Influences, 36 Early-20th-Century Medicine, 38 The Metamorphosis of Orthodox Medicine, 38 The Halcyon Years of Naturopathy, 38 The Emerging Dominance of American Medical Association Medicine, 40 The Modern Rejuvenation, 44 The 21st Century Awaits, 46

Editors’ Note: This is the first of two chapters comprehensively presenting the origins and evolution of naturopathic medicine. Quotes from key historical figures are used extensively in both chapters to illustrate how the ideas of naturopathic medicine originated and evolved. One challenge with this approach is that the language use and terminology more than a century ago are somewhat different from the current vocabulary. In addition, these pioneers were limited by the very early stages of the biological sciences because rigorous research into physiology and pathology was just beginning. Thus, from the modern perspective, some ideas may seem quaint, awkward, or “unscientific” based on our current understanding. Nonetheless, the concepts of health and disease they developed, despite the limited biological research, were remarkably insightful and, as well demonstrated by the more than 200 chapters in this textbook, have almost all now been fully validated. In fact, a number of their dire predictions of increased incidence of chronic disease if conventional medicine practices became dominant have now been conclusively demonstrated to have been correct. We urge the reader to focus on the evolution of the concepts and not be distracted by the antiquated terminology.

forerunners of these concepts already existed in the history of natural healing, both in America and in the Austro-Germanic European core. Lust came to this country from Germany in the 1890s as a disciple of Father Sebastian Kneipp, a Dominican priest, and as an emissary dispatched by Father Kneipp to bring hydrotherapy to America. Lust purchased the term naturopathy from Scheel in 1902 to describe the eclectic compilation of doctrines of natural healing that he envisioned to be the future of natural medicine. In January 1902, Lust, who had been publishing the Kneipp Water Cure Monthly and its Germanlanguage counterpart in New York since 1896, changed the name of the journal to The Naturopath and Herald of Health and evoked the dawn of a new health care era with the following editorial:

INTRODUCTION Naturopathy, as a generally used term, emerged in America from the writings and promotion of Benedict Lust. Naturopathy, or “nature cure,” is both a way of life and a concept of healing that employs various natural means of treating human infirmities and disease states. The earliest mechanisms of healing associated with the term, as used by Lust, involved a combination of hygienics and hydropathy (hydrotherapy). The term itself was coined in 1895 by Dr. John Scheel of New York City to describe his method of health care. However, earlier * Previous edition contributor

Naturopathy is a hybrid word. It is purposely so. No single tongue could distinguish a system whose origin, scope and purpose is universal—broad as the world, deep as love, high as heaven. Naturopathy was not born of a sudden or a happen-so. Its progenitors have for eons been projecting thoughts and ideas and ideals whose culminations are crystallized in the new Therapy. Connaro, doling out his few fixed ounces of food and drink each day in his determined exemplification of Dietotherapy; Priessnitz, agonizing, despised and dejected through the long years of Hydropathy’s travail; the Woerishofen priest, laboring lovingly in his little parish home for the thousands who journeyed Germany over for the Kneipp cure; Kuhne, living vicariously and dying a martyr for the sake of Serotherapy; A.T. Still, studying and struggling and enduring for his faith in Osteopathy; Bernarr Macfadden, fired by the will to make Physical Culture popular; Helen Willmans, threading the mazes of Mental Science, and finally emerging triumphant; Orrison Sweet Maraden, throbbing in sympathy with human faults and failures, and longing to realize Success to all mankind—these and hosts of

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others have brought into being single systems whose focal features are perpetuated in Naturopathy. Jesus Christ—I say it reverently—knew the possibility of physical immortality. He believed in bodily beauty; He founded Mental Healing; He perfected Spirit-power. And Naturopathy will include ultimately the supreme forces that made the Man of Galilee omnipotent.The scope of Naturopathy is from the first kiss of the new-found lovers to the burying of the centenarian whose birth was the symbol of their perfected one-ness. It includes ideally every life-phase of the id, the embryo, the foetus, the birth, the babe, the child, the youth, the man, the lover, the husband, the father, the patriarch, the soul. We believe in strong, pure, beautiful bodies thrilling perpetually with the glorious power of radiating health. We want every man, woman and child in this great land to know and embody and feel the truths of right living that mean conscious mastery. We plead for the renouncing of poisons from the coffee, white flour, glucose, lard, and like venom of the American table to patent medicines, tobacco, liquor and the other inevitable recourse of perverted appetite. We long for the time when an eight-hour day may enable every worker to stop existing long enough to live; when the spirit of universal brotherhood shall animate business and society and the church; when every American may have a little cottage of his own, and a bit of ground where he may combine Aerotherapy, Heliotherapy, Geotherapy, Aristophagy and nature’s other forces with home and peace and happiness and things forbidden to flat-dwellers; when people may stop doing and thinking and being for others and be for themselves; when true love and divine marriage and pre-natal culture and controlled parenthood may fill this world with germ-gods instead of humanized animals.In a word, Naturopathy stands for the reconciling, harmonizing and unifying of nature, humanity and God. Fundamentally therapeutic because men need healing; elementally educational because men need teaching; ultimately inspirational because men need empowering, it encompasses the realm of human progress and destiny. Perhaps a word of appreciation is due Mr. John H. Scheel, who first used the term “Naturopathic” in connection with his Sanitarium “Badekur,” and who has courteously allowed us to share the name. It was chosen out of some 150 submitted, as most comprehensive and enduring. All our present plans are looking forward some five or ten or fifty years when Naturopathy shall be the greatest system in the world. Actually the present development of Naturopathy is pitifully inadequate, and we shall from time to time present plans and ask suggestions for the surpassing achievement of our world-wide purpose. Dietetics, Physical Culture and Hydropathy are the measures upon which Naturopathy is to build; mental culture is the means, and soul-selfhood is the motive. If the infinite immensity of plan, plea and purpose of this particular magazine and movement were told you, you would simply smile in your condescendingly superior way and straightway forget. Not having learned as yet what a brain and imagination and a will can do, you consider Naturopathy an ordinarily innocuous affair, with a lukewarm purpose back of it, and an ebbing future ahead of it. Such is the character of the average wishy-washy health movement and tumultuous wave of reform. Your incredulous smile would not discomfit us—we do not importune your belief, or your help, or your money. Wherein we differ from the orthodox self-labeled reformer, who cries for sympathy and cringes for shekels. We need money most persistently—a million dollars could be used to advantage in a single branch of the work already definitely planned and awaiting materialization; and we need co-operation

in a hundred different ways. But these are not the things we expect or deem best. Criticism, fair, full and unsparing is the one thing of value you can give this paper. Let me explain. Change is the keynote of this January issue—in form, title, make-up. If it please you, your subscription and a word to your still-benighted friends is ample appreciation. But if you don’t like it, say so. Tell us wherein the paper is inefficient or redundant or ill-advised, how it will more nearly fit into your personal needs, what we can do to make it the broadest, deepest, truest, most inspiring of the mighty host of printed powers. The most salient letter of less than 300 words will be printed in full, and we shall ask to present the writer with a subscription-receipt for life. By to-morrow you will probably have forgotten this request; by the day after you will have dropped back into your old ways of criminal eating and foolish drinking and sagged standing and congested sitting and narrow thinking and deadly fearing—until the next progress paper of New Thought or Mental Science or Dietetics or Physical Culture prods you into momentary activity. Between now and December we shall tell you just how to preserve the right attitude, physical and mental, without a single external aid; and how, every moment of every day, to tingle and pulsate and leap with the boundless ecstasy of manhood consciously nearing perfection. 

A BRIEF HISTORY OF EARLY AMERICAN MEDICINE WITH AN EMPHASIS ON NATURAL HEALING To understand the evolutionary history of naturopathic medicine in this country, it is necessary to view the internal development of the profession against the historical, social, and cultural backdrop of American social history.

Medicine in America: 1800–1875 In the America of 1800, although a professional medical class existed, medicine was primarily domestically oriented. An individual who fell ill was commonly nursed by a friend or family member who relied upon William Buchan’s Domestic Medicine (1769), John Wesley’s Primitive Physic (1747), or John Gunn’s Domestic Medicine (1830).1

Professional Medicine Professional medicine transferred from England and Scotland to America in prerevolutionary days. However, 18th- and early-19th-century America considered the concept of creating a small, elite, learned profession to run counter to the political and institutional concepts of early American democracy.1 The first medical school in the American colonies opened in 1765 at what was then the College of Philadelphia (later the University of Pennsylvania), and the school was dominated by revolutionary leader and physician Benjamin Rush, a signatory to the Declaration of Independence. The proliferation of medical schools to train the new professional medical class began seriously after the war of 1812. Between 1810 and 1820, new schools were established in Baltimore, Lexington, Cincinnati, and even in rural communities in Vermont and Western New York. Between 1820 and 1850, substantial numbers of schools were established in the western rural states. By 1850, there were 42 medical schools recognized in the United States, although there were only 3 in all of France. Generally, these schools were started by a group of five to seven local physicians approaching a local college with the idea of establishing a medical school in conjunction with the college’s educational facilities. The schools were largely apprenticeship based, and the professors received their remuneration directly from fees paid by the students.

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

The requirements for a doctor of medicine (MD) degree in late18th- and early-19th-century America were roughly as follows: • Knowledge of Latin and natural and experimental philosophy • Three years of serving an apprenticeship under practicing physicians • Attending two terms of lectures and passing of attendant examinations • A thesis Additionally, graduating students had to be at least 21 years of age.1 The rise of any professional class is gradual and marked by difficulties, and varying concepts existed as to the demarcation of a “professional” physician. Contrasts included graduates of medical school versus nongraduates, medical society members versus nonmembers, and licensed physicians versus unlicensed “doctors.” Licensing statutes came into existence between 1830 and 1850 but were soon repealed because they were considered “undemocratic” during the apex of Jacksonian democracy. 1 

Thomsonianism In 1822 the rise in popularity of Samuel Thomson and his publication of New Guide to Health helped frustrate the creation of a professional medical class. Thomson’s work was a compilation of his personal view of medical theory and American Indian herbal and medical botanical lore. Thomson espoused the belief that disease had one general cause—“cold” influences on the human body—and that disease therefore had one general remedy: “heat.” Unlike the followers of Benjamin Rush and the American “heroic” medical tradition who advocated blood-letting, leeching, and the substantial use of mineral-based purgatives such as antimony and mercury, Thomson believed that minerals were sources of “cold” because they came from the ground and that vegetation, which grew toward the sun, represented “heat.” 1 As noted in Griggs’s Green Pharmacy (the best history of herbal medicine to date), Thomson’s theory developed as follows2: Instead, he elaborated a theory of his own, of the utmost simplicity: “All diseases … are brought about by a decrease or derangement of the vital fluids by taking cold or the loss of animal warmth … the name of the complaint depends upon what part of the body has become so weak as to be affected. If the lungs, it is consumption, or the pleura, pleurisy; if the limbs, it is rheumatism, or the bowels, colic or cholera morbus … all these different diseases may be removed by a restoration of the vital energy, and removing the obstructions which the disease has generated …” Thus the great object of his treatment was always to raise and restore the body’s vital heat: “All … that medicine can do in the expulsion of disorder, is to kindle up the decaying spark, and restore its energy till it glows in all its wonted vigor.” Thomson’s view was that individuals could be self-treating if they had a sincere “guide to health” philosophy and a copy of his book, New Guide to Health. The right to sell “family franchises” for the use of the Thomsonian method of healing was the basis of a profound lay movement between 1822 and Thomson’s death in 1843. Thomson adamantly believed that no professional medical class should exist and that democratic medicine was best practiced by laypersons within a Thomsonian “family” unit. By 1839, Thomson claimed to have sold some 100,000 of these family franchises called “friendly botanic societies.” Although he professed to have solely the interests of the individual at heart, his system was sold at a profit under the protection of a patent he obtained in 1813. 

The Eclectic School of Medicine Some of the “botanics” (professional Thomsonian doctors) wanted to separate themselves from the lay movement by creating requirements

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and standards for the practice of Thomsonian medicine. Thomson, however, was adamantly against a medical school founded on his views. Thus it was not until the decade after Thomson’s death that independent Thomsonians founded a medical college (in Cincinnati) and began to dominate the Thomsonian movement. These Thomsonian botanics were later absorbed into the medical sectarian movement known as the “eclectic school,” which originated with the New Yorker Wooster Beach. Beach was another of medical history’s fascinating characters. From a well-established New England family, he started his medical studies at an early age, apprenticing under an old German herbal doctor, Jacob Tidd. After Tidd died, Beach enrolled in the Barclay Street Medical University in New York. Griggs2 described the following: Beach’s burning ambition was to reform medical practice generally—not to alienate the entire profession by savage attacks from without—and he was convinced that he would be in a stronger position to do so if he were himself a diplomatized doctor. The faculty occasionally listened to criticism from within their own number: against onslaughts of “illiterate quacks” like Samuel Thomson, they simply closed ranks in complacent hostility. After opening his own practice in New York, Beach set out to win over fellow members of the New York Medical Society (into which he had been warmly introduced by the screening committee) to his point of view that heroic medicine was inherently dangerous to mankind and should be reduced to the gentler theories of herbal medicine. He was summarily ostracized from the medical society. To Beach, this was a bitter blow, but he soon founded his own school in New York, calling the clinic and educational facility the “United States Infirmary.” However, because of continued pressure from the medical society, he was unable to obtain charter authority to issue legitimate diplomas. He then located a financially ailing but legally chartered school, Worthington College, in Ohio. He opened a full-scale medical college; out of its classrooms, he launched what became known as the Eclectic School of Medical Theory. Griggs related the following2: Beach had a new name for his practice: While explaining to a friend his notions of combining what was useful in the old practice with what was best in the new, the friend exclaimed, “You are an eclectic!” to which, according to legend, Beach replied, “You have given me the term which I have wanted: I am an eclectic!” Cincinnati subsequently became the focal point of the eclectic movement, and the E. M. Institute medical school remained until 1938 (the last eclectic school to exist in America).3 The concepts of this sect helped form some of the theoretical underpinnings of Lust’s naturopathy. Lust himself graduated from the Eclectic Medical College of the City of New York in the first decade of the 1900s. Despite his criticism of the early allopathic movement (although the followers of Rush were not yet known as allopaths, a term reputed to have been coined by Samuel Hahnemann) for their “heroic” tendencies, Thomson’s medical theories were “heroic” in their own fashion. Although he did not advocate blood-letting, heavy metal poisoning, and leeching, botanic purgatives—particularly Lobelia inflata (Indian tobacco)—were a substantial part of the therapy. 

The Hygienic School of Thought One other forerunner of American naturopathy, also originating as a lay movement, grew into existence at this time. This was the “hygienic” school, which had its genesis in the popular teachings of Sylvester Graham and William Alcott. Graham began preaching the doctrines of temperance and hygiene in 1830. In 1839 he published Lectures on the Science of Human Life,

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two hefty volumes that prescribed healthy dietary habits. He emphasized a moderate lifestyle, recommending an antiflesh diet and bran bread as an alternative to bolted or white bread. Alcott dominated the scene in Boston during this same period and, together with Graham, saw that the American hygienic movement—at least as a lay doctrine—was well established.4 

Homeopathy By 1840, the profession of homeopathy had also been transplanted to America from Germany. Homeopathy, the creation of an early German physician, Samuel Hahnemann (1755–1843), had three central doctrines: • The “law of similars” (that like cures like) • That the effect of a medication could be heightened by its administration in minute doses (the more diluted the dose, the greater the “dynamic” effect) • That nearly all diseases were the result of a suppressed itch, or “psora” The view was that a patient’s natural symptom-producing disease would be displaced after homeopathic medication by a similar, but much weaker, artificial disease that the body’s immune system could easily overcome. Originally, most homeopaths in this country were converted orthodox medical men, or “allopaths.” The high rate of conversion made this particular medical sect the archenemy of the rising orthodox medical profession. (For a more detailed discussion of homeopathy, see Chapter 39.) The first homeopathic medical school was founded in 1850 in Cleveland; the last purely homeopathic medical school, based in Philadelphia, survived into the early 1930s. 1 

The Rise and Fall of the Sects Although these two nonallopathic sects were popular, they never comprised more than one fifth of the professional medical class in America. Homeopathy at its highest point reached roughly 15% and the eclectic school roughly 5%. However, their very existence for many years kept the exclusive recognition desired by the orthodox profession from coming within its grasp. Homeopathy was distasteful to the more conventional medical men not only because it resulted in the conversion of a substantial number of their peers but also because homeopaths generally also made a better income. The rejection of the eclectic school was more fundamental: it had its roots in a lay movement that challenged the validity of a privileged professional medical class. The existence of three professional medical groups—the orthodox school, the homeopaths, and the eclectics—combined with the Jacksonian view of democracy that prevailed in mid-19th-century America, resulted in the repeal of virtually all medical licensing statutes existing before 1850. However, by the 1870s and 1880s, all three medical groups began to voice support for the restoration of medical licensing. Views differ as to what caused the homeopathic and eclectic schools to disappear from the medical scene in the 50 years after 1875. One view defined a sect as follows5: A sect consists of a number of physicians, together with their professional institutions, who utilize a distinctive set of medically invalid therapies which are rejected by other sects. By this definition, the orthodox or allopathic school was just as sectarian as the homeopathic and eclectic schools. Rothstein’s view was that these two 19th-century sects disappeared because, beginning in the 1870s, the orthodox school grasped the European idea of “scientific medicine.” Based on the research of such men as Pasteur and Koch and the “germ theory,” this approach supposedly proved to be the

medically proper view of valid therapy and gained public recognition because of its truth. Another view was that the convergence of the needs of the three sects for professional medical recognition (which began in the 1870s and continued into the early 1900s) and the “progressive era” led to a political alliance in which the majority orthodox school was ultimately dominant by sheer weight of numbers and internal political authority. Starr1 noted the following: Both the homeopaths and eclectics wanted to share in the legal privileges of the profession. Only afterward did they lose their popularity. When homeopathic and eclectic doctors were shunned and denounced by the regular profession, they thrived, but the more they gained an access to the privileges of regular physicians, the more their numbers declined. The turn of the century was both the point of acceptance and the moment of incipient disintegration. In any event, this development was an integral part of the drive toward professional authority and autonomy established during the progressive era (1900–1917). It was acceptable to the homeopaths and the eclectics because they controlled medical schools that continued to teach and maintain their own professional authority and autonomy. However, it was after these professional goals were attained that the lesser schools of medical thought went into rapid decline. 1 

The American Influence From 1850 to 1900, the medical counterculture continued to establish itself in America. From its lay roots in the teachings of the hygienic movement grew professional medical recognition, albeit a small minority and “irregular” view, that hygiene and hydropathy were the basis of sound medical thought (much like the Thomsonian transition to botanic and eclectic medicine).

Russell Trall The earliest physician who had a significant effect on the later growth of naturopathy as a philosophic movement was Russell Trall, MD. As noted in James Whorton’s Crusaders for Fitness,4 he “passed like a meteor through the American hydropathic and hygienic movement”: The exemplar of the physical educator-hydropath was Russell Thatcher Trall. Still another physician who had lost his faith in regular therapy, Trall opened the second water cure establishment in America, in New York City in 1844. Immediately he combined the full Preissnitzian armamentarium of baths with regulation of diet, air, exercise and sleep. He would eventually open and or direct any number of other hydropathic institutions around the country, as well as edit the Water-Cure Journal, the Hydropathic Review, and a temperance journal. He authored several books, including popular sex manuals which perpetuated Graham-like concepts into the 1890s, sold Graham crackers and physiology texts at his New York office, was a charter member (and officer) of the American Vegetarian Society, presided over a short-lived World Health Association, and so on. His crowning accomplishment was the Hygeian Home, a “model Health Institution [which] is beautifully situated on the Delaware River between Trenton and Philadelphia.” A drawing presents it as a palatial establishment with expansive grounds for walking and riding, facilities for rowing, sailing, and swimming, and even a grove for open-air “dancing gymnastics.” It was the grandest of water cures, and lived beyond the Civil War period, which saw the demise of most hydropathic hospitals. True, Trall had to struggle to keep his head above water during the 1860s, but by the 1870s he had a firm financial footing (being stabilized by tuition fees from the attached Hygeio-therapeutic College). With Trall’s death in 1877, however, the hydropathic phase of health reform passed.

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

As made evident later in this chapter, this plethora of activity was similar to that engaged in by Benedict Lust between 1896 and his death in 1945, when he worked to establish naturopathy. The Hygeian Home and later “Yungborn” establishments at Butler, New Jersey, and Tangerine, Florida, were similar to European nature cure sanitariums, such as the original Yungborn founded by Adolph Just and the spa/ sanitarium facilities of Preissnitz, Kneipp, and Just. Trall gave a famous address to the Smithsonian Institution in Washington, DC, in 1862, under the sponsorship of the Washington Lecture Association. “The true healing art: or hygienic vs drug medication,” a 2.5-hour lecture purported to have received rapt attention, was devoted to Trall’s belief in the hygienic system and in hydropathy as the true healing art. The address was reprinted by Fowler and Wells (New York, 1880) with an introduction written by Trall, before his death in 1877. Trall also founded the first school of natural healing arts in this country to have a 4-year curriculum and the authorization to confer the degree of MD. It was founded in 1852 as a “hydropathic and physiological school” and was chartered by the New York State Legislature in 1857 under the name “New York Hygio-Therapeutic College,” with the legislature’s authorization to confer the MD degree. In 1862 Trall went to Europe to attend the International Temperance Convention. He took a prominent part at this meeting of reformers, specifically related to the use of alcohol as a beverage and as a medicine. He eventually published more than 25 books on the subjects of physiology, hydropathy, hygiene, vegetarianism, and temperance, among many others. The most valuable and enduring of these was his Hydropathic Encyclopedia, a volume of nearly 1000 pages that covered the theory and practice of hydropathy and the philosophy and treatment of diseases advanced by older schools of medicine. At the time of his death, according to the December 1877 Phrenological Journal cover article featuring a lengthy obituary of Trall, this encyclopedia had sold more than 40,000 copies since its original publication in 1851. For more than 15 years, Trall was editor of the Water-Cure Journal (also published by Fowler and Wells). During this period, the journal went through several name changes, including the Hygienic Teacher and The Herald of Health. When Lust originally opened the American School of Naturopathy, an English-language version of Kneipp’s Water-cure (or Meine Wasser-kurr in German) being unavailable, he used only the works and writings of Trall as his texts. 

Martin Luther Holbrook By 1871, Trall moved from New York to the Hygeian Home on the Delaware River. His water-cure establishment in New York became the New Hygienic Institute. One of its coproprietors was Martin Luther Holbrook, who later replaced Trall as the editor of The Herald of Health. Professor Whorton noted the following4: But Holbrook’s greatest service to the cause was as an editor. In 1866 he replaced Trall at the head of The Herald of Health, which had descended from the Water-Cure Journal and Herald of Reforms (1845–1861) by the way of the Hygienic Teacher and Water-Cure Journal (1862). Under Holbrook’s direction the periodical would pass through two more name changes (Journal of Hygiene Herald of Health, 1893–1897, and Omega, 1898–1900) before merging with Physical Culture. Trall and Holbrook both advanced the idea that physicians should teach the maintenance of health rather than simply providing a last resort in times of health crisis. Besides providing a strong editorial voice espousing vegetarianism, the evils of tobacco and drugs, and the value of bathing and exercise, dietetics and nutrition, along with

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personal hygiene, were strongly advanced by Holbrook and others of the hygienic movement during this era. Whorton described the idea as follows4: The orthodox hygienists of the progressive years were equally enthused by the recent progress of nutrition, of course, and exploited it for their own ends, but their utilization of science hardly stopped with dietetics. Medical bacteriology was another area of remarkable discovery, bacteriologists having provided, in the short space of the last quarter of the 19th century, an understanding, at long last, of the nature of infection. This new science’s implications for hygienic ideology were profound—when Holbrook locked horns with female fashion, for example, he did not attack the bulky, ground-length skirts still in style with the crude Grahamite objection that the skirt was too heavy. Rather he forced a gasp from his readers with an account of watching a smartly dressed lady unwittingly drag her skirt “over some virulent, revolting looking sputum, which some unfortunate consumptive had expectorated.” Holbrook expanded on the work of Graham, Alcott, and Trall and, working with an awareness of the European concepts developed by Preissnitz and Kneipp, laid further groundwork for the concepts later advanced by Lust, Lindlahr, and others4: For disease to result, the latter had to provide a suitable culture medium, had to be susceptible. As yet, most physicians were still so excited at having discovered the causative agents of infection that they were paying less than adequate notice to the host. Radical hygienists, however, were bent just as far in the other direction. They were inclined to see bacteria as merely impotent organisms that throve only in individuals whose hygienic carelessness had made their body compost heaps. Tuberculosis is contagious, Holbrook acknowledged, but “the degree of vital resistance is the real element of protection. When there is no preparation of the soil by heredity, predisposition or lowered health standard, the individual is amply guarded against the attack.” A theory favored by many others was that germs were the effect of disease rather than its cause; tissues corrupted by poor hygiene offered microbes, all harmless, an environment in which they could thrive. In addition to introducing the works of Kneipp and his teachings to the American hygienic healthcare movement, Holbrook was a leader of the fight against vivisection and vaccination4: Vivisection and vaccination were but two of the practices of medicine criticized in the late 19th century. Therapy also continued to be an object of protest. Although the heroism of standard treatment had declined markedly since mid-century, a prescription was still the reward of any visit to the doctor, and drugless alternatives to healing were appearing in protest. Holbrook published frequent favorable commentaries on the revised water cure system of Germany’s Kneipp. A combination of baths, herbal teas, and hardening exercises, the system had some vogue in the 1890’s before flowering into naturopathy. Holbrook’s journal also gave positive notices to osteopathy and “chiropathy” [chiropractic], commending them for not going to the “drugstore or ransack[ing] creation for remedies nor load[ing] the blood with poison.” But though bathing and musculoskeletal manipulation were natural and nonpoisonous, Holbrook preferred to give the body complete responsibility for healing itself. Rest and proper diet were the medicines of this doctor who billed himself as a “hygienic physician” and censured ordinary physicians for being engrossed with disease rather than health. 

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Philosophy of Natural Medicine

The Beginnings of “Scientific Medicine”

Medical Education in Transition

While the hygienic movement was making its effect, the orthodox medical profession, in alliance with the homeopaths and eclectics, was making significant advances. The orthodox profession, through the political efforts of the American Medical Association (AMA), first tried to remove sectarian and irregular practitioners by segregating them from the medical profession altogether. It did so by formulating and publishing its first national medical code of ethics in 1847. (In 1846 the orthodox profession formed the AMA to represent its professional views.) The code condemned proprietary patents (even carrying over into a physician’s development of surgical or other medical implements, which led to its greatest criticism); encouraged the adoption of uniform rules for payment in geographic areas; condemned the practice of contract work; prohibited advertising and fee-sharing even among specialists and general practitioners; eliminated blacks and women; and, most significantly, prohibited any consultation or contact with irregulars or sectarian practitioners. The code stated the following6:

Based on the rising example of scientific medicine and its necessary connection to research, the educational laboratory, and a more thorough scientific education as a preamble to medical practice, Harvard University (under the presidency of Charles Elliott) created a 4-year medical educational program in 1871. The primal modern medical educational curriculum was devised and set in motion more than 20 years later at Johns Hopkins University under the leadership of William Osler and William Welch, using the resources from the original endowment of the hospital and university from the estate of Johns Hopkins.1 Other schools followed suit. By the time the AMA set up its Council on Medical Education in 1904, it was made up of five members from the faculties of schools modeled on the Johns Hopkins prototype. This committee set out to visit and rate each of the 160 medical schools then in operation in the country. The ratings used were class A (acceptable), class B (doubtful), and class C (unacceptable). Eighty-two schools received a class A rating, led by Harvard, Rush (Chicago), Western Reserve, the University of California, and notably, Johns Hopkins. Forty-six schools received a class B rating, and 32 received a class C rating. The class C schools were mostly in rural areas, and many of them were proprietary in nature. 

No one can be considered as a regular practitioner, or a fit associate in consultation, whose practice is based on an exclusive dogma, to the rejection of the accumulated experience of the profession, and of the aids actually furnished by anatomy, physiology, pathology, and organic chemistry. In the late 1870s and into the 1880s the major sects—the orthodox or allopathic school, the homeopaths, and the eclectics—began to find more reason to cooperate to obtain common professional goals. These included the enactment of new licensing laws and the creation of a “respectable” medical educational system. Also at this time, the concept of “scientific medicine” was brought to America. (Although Starr differed from Rothstein regarding the causes of the decline of the homeopathic and eclectic sectarian schools, he noted that Rothstein clearly documented the 19th-century transition of medicine into a recognized professional class composed of both the minority sects and the orthodox school.) This transition from conflict between the major sects resulted in the erosion of the implementation of the code of ethics; the cooperation among the sects to revive medical licensing standards; the admission of sectarian physicians to regular medical societies; and ultimately, a structural reorganization of the AMA, which occurred between 1875 and 1903.15 Once the cooperation among the three medical views began, the medical class dominated by the regular school came fully into power. The homeopathic and eclectic schools of thought met their demise finally because of two significant events: (1) the rapid creation of new medical educational standards between 1900 and 1910, culminating in the publication of the famous “Flexner Report” (1910), and (2) the effective infusion of millions of dollars into selected allopathic medical schools by the newly created capitalistic philanthropic foundations, principally the Carnegie and Rockefeller Foundations.

The Foundations The effect of the monies from the Carnegie and Rockefeller Foundations was clearly documented7 and described in detail in Brown’s Rockefeller Medicine Men.8 The effect of the monies from these foundations, contributed to medical schools that met the AMA’s views on medical education and philosophy, cannot be underestimated. This process has been well documented.1,7,9,10 As discussed by Burrows,10 these educational reforms allowed the AMA to forge a new alliance with state legislators and push quickly for medical licensing designed to reward the educational and medical expertise of the newly orthodox “scientific medicine” and to the exclusion of all others. 

Flexner Report Subsequent to the AMA ratings, the Council on Medical Education applied to the Carnegie Foundation to commission an independent report to verify its work. Abraham Flexner, a young, energetic, and noted educator, was chosen for this task by the Carnegie Foundation and accompanied by the secretary (Nathan Colwell, MD) of the Council on Medical Education, who participated in all of the committee site visits. Flexner visited each of the 162 operating U.S. medical schools. The widely publicized Flexner Report put the nails in the coffins of all schools with class C ratings and many with class B ratings. Significantly, the educational programs of all but one eclectic school (in Cincinnati) and one homeopathic school (in Philadelphia) were eliminated by 1918. The eclectic medical schools, in particular, were severely affected by the report. Griggs explained this effect as follows2: Of the eight Eclectic schools, the Report declared that none had “anything remotely resembling the laboratory equipment which is claimed in their catalogs.” Three of them were under-equipped; the rest “are without exception filthy and almost bare. They have at best grimy little laboratories … a few microscopes, some bottles containing discolored and unlabeled pathological material, in an incubator out of commission, and a horrid dissecting room.” The Report found them more culpable than a regular school for these inadequacies: “… the Eclectics are drug-mad; yet, with the exception of the Cincinnati and New York schools, they are not equipped to teach the drugs or drug therapy which constitutes their sole reason for existence.” The other regular schools that conducted homeopathic or eclectic programs had by that time phased them out in the name of “scientific medicine” (see also Haller3). 

Pharmaceutical Industry During this same time, the AMA, through several of its efforts, began a significant alliance with the organized pharmaceutical industry of the United States, shaping it in a manner acceptable to the allopathic profession.1,9,11 

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

The New “Sects” The period from 1890 to 1905 saw the rise of three new medical sects and several other smaller “irregular” schools that replaced those soon to pass from the scene. In Missouri, Andrew Taylor Still, originally trained as an orthodox practitioner, founded the school of medical thought known as “osteopathy” and in 1892 opened the American School of Osteopathy in Kirksville, Missouri. In 1895 Daniel David Palmer, originally a magnetic healer from Davenport, Iowa, performed the first spinal manipulation, which gave rise to the school he termed “chiropractic.” He formally published his findings in 1910, after having founded a chiropractic school in Davenport, Iowa. In 1902 Lust founded the American School of Naturopathy in New York. Although some of the following discussions are devoted to the schools of healing called osteopathy and chiropractic, only that portion of their histories related to the history of naturopathy is mentioned.12 (A full study of osteopathic medicine in America may be found in The D.O.’s by Gevitz,13 and a reasonable sketch of chiropractic medicine may be found in Kapling’s chapter in Alternative Medicine.12) As noted by Starr,1 these new sects, including Christian Science, formulated by Mary Baker Eddy,14 either rose or fell on their own without ever completely allying with orthodox medicine. Starr theorized that these sects arose late enough that the orthodox profession and its political action arm, the AMA, had no need to ally with them and would rather battle with them publicly. This made these sectarian views separate and distinct from the homeopathic and eclectic schools. 

THE FOUNDING OF NATUROPATHIC MEDICINE Benedict Lust Lust came to the United States in 1892 at the age of 23. He suffered from a debilitating condition in his late teens while growing up in Michelbach, Baden, Germany, and was sent by his father to undergo the Kneipp cure at Woerishofen. He stayed there from mid-1890 to early 1892; not only was he “cured” of his condition, but he also became a protégé of Kneipp. Dispatched by Kneipp to bring the principles of the Kneipp water cure to America, he emigrated to New York City. By making contact in New York with other German Americans who were also becoming aware of the Kneipp principles, Lust participated in the founding of the first “Kneipp Society,” which was organized in Jersey City, New Jersey, in October 1896. Lust also attended the first organizational meeting (in mid-October 1896) of the Kneipp Society of Brooklyn. Subsequently, through Lust’s organization and contacts, Kneipp Societies were founded in Boston; Chicago; Cleveland; Denver; Cincinnati; Philadelphia; Columbus; Buffalo and Rochester, New York; New Haven, Connecticut; San Francisco; New Mexico; and Mineola on Long Island, New York. The members of these organizations were provided with copies of the Kneipp Blatter and a companion English publication Lust began to put out called The Kneipp Water Cure Monthly. The first “sanatorium” using Kneipp’s principles was organized in this country shortly before Lust’s arrival. Charles Lauterwasser, an earlier student of Kneipp’s who called himself a hydrothic physician and natural scientist, opened the Kneipp and Nature Cure Sanatorium in Newark, New Jersey, in 1891. In 1895 the Brooklyn Light and Water-Cure Institute was established in Brooklyn, New York, by L. Staden and his wife Carola, both graduates of Lindlahr’s Hygienic College in Dresden, Germany. According to their advertising, they specialized in natural healing, Kneipp water treatment, and Kuhne’s and Preissnitz’s principles (including diet cure, electric light baths [both white and blue], electric vibration massage, Swedish massage and movements, and Thure Brandt massage).

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In 1895 Lust opened the Kneipp Water-Cure Institute in New York City, listing himself as the owner and Dr. William Steffens as the residing physician. At the same address (on 59th Street) in October of that year, Lust opened the first “Kneipp store.” In the originating November 1896 edition of The Kneipp Water Cure Monthly and Kneipp Blatter, he advertised his store and sanitarium as personally authorized by Kneipp. In the first part of 1896, just before his organizing of various Kneipp Societies around the New York area, Lust returned to Woerishofen to study further with Kneipp. Kneipp died in Germany, at Woerishofen, in June 1897. With his passing, Lust was no longer bound strictly to the principles of the Kneipp water cure. He had begun to associate earlier with other German American physicians, principally Dr. Hugo R. Wendel (a German-trained Naturarzt), who began, in 1897, to practice in New York and New Jersey as a licensed osteopathic physician. In 1896 Lust entered the Universal Osteopathic College of New York, graduated in 1898, and became licensed as an osteopathic physician. In 1897 Lust became an American citizen. Once he was licensed to practice as a healthcare physician in his own right, Lust began the transition toward the concept of “naturopathy.” Between 1898 and 1902, when he adopted the term naturopath, Lust acquired a chiropractic education and changed the name of his Kneipp store to the Health Food Store (the original facility to use that name and concept in this country), specializing in providing organic foods and the materials necessary for drugless cures. He also began the New York School of Massage (listed as established in 1896) and the American School of Chiropractic, all within the same facility—Lust’s Kneipp Institute. Photographs of this facility taken between 1902 and 1907, when the facility moved to another location, show a five-story building listing “Benedict Lust—Naturopath, Publisher, Importer.” He returned to Germany in 1907 to visit with Dr. Baumgarten, Kneipp’s medical successor at the Woerishofen facility, which was then run, in cooperation with Baumgarten, by the Reverend Prior Reily, the former secretary to Kneipp and his lay successor at Woerishofen. As directed by Kneipp, Reily had completed, after Kneipp’s death, Kneipp’s masterwork Das grosse Kneipp—Buch. Lust maintained contact with the partnership of Reily and Baumgarten throughout the early part of the 20th century. In 1902 when he purchased and began using the term naturopathy and calling himself a “naturopath,” Lust, in addition to his New York School of Massage and American School of Chiropractic, his various publications, and his operation of the Health Food Store, began to operate the American School of Naturopathy, all at the same 59th Street New York address. By 1907 Lust’s enterprises had grown sufficiently large that he moved them to a 55-room building. It housed the Naturopathic Institute, Clinic, and Hospital; the American Schools of Naturopathy and Chiropractic; the now-entitled Original Health Food Store; Lust’s publishing enterprises; and the New York School of Massage. The operation remained in this four-story building, roughly twice the size of the original facility, from 1907 to 1915. From 1912 to 1914, Lust took a “sabbatical” from his operations to further his medical education. By this time, he had founded his large estate-like sanitarium in Butler, New Jersey, known as “Yungborn” after the German sanitarium operation of Adolph Just. In 1912 he attended the Homeopathic Medical College in New York, which, in 1913, granted him a degree in homeopathic medicine, and in 1914, he received his degree in eclectic medicine. In early 1914 Lust traveled to Florida and obtained an MD’s license on the basis of his graduation from the Homeopathic Medical College and the Eclectic Medical College of New York City.

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Philosophy of Natural Medicine

He founded another “Yungborn” sanitarium facility in Tangerine, Florida, and for the rest of his life, while continuing his publications, he engaged in active public lecturing. He also continued to maintain a practice in New York City and operated the sanitariums in Florida and New Jersey. His schools were operated primarily by Hugo R. Wendel. From 1902, when he began to use the term naturopathy, until 1918, Lust replaced the Kneipp Societies with the Naturopathic Society of America. Then, in December 1919, the Naturopathic Society of America was formally dissolved because of its insolvency, and Lust founded the American Naturopathic Association (ANA). Thereafter, 18 states incorporated the association. In 1918, as part of his effort to replace the Naturopathic Society of America (an operation into which he invested a great deal of his funds and resources in an attempt to organize a naturopathic profession) and replace it with the ANA, Lust published the first Universal Naturopathic Directory and Buyer’s Guide (a “yearbook of drugless therapy”). Although a completely new version was never actually published, despite Lust’s announced intention to make this volume an annual publication, annual supplements were published in either The Naturopath and Herald of Health or its companion publication Nature’s Path (which commenced publication in 1925). The Naturopath and Herald of Health, sometimes printed with the two phrases reversed, was published from 1902 to 1927 and from 1934 until after Lust’s death in 1945. This volume documented the merging of the German and American influences that guided Lust in his development of the practice of naturopathy. The voluminous tome, which ran to 1416 pages, was dedicated to: The memory of all those noble pioneers and discoverers who have died in the faith of Naturopathy, and to their courageous successors in the art of drugless healing, all of whom have suffered persecution for saving human lives that medical autocracy could not save, this work is respectfully dedicated by its editor Benedict Lust, N.D., M.D., “The Yungborn,” Butler, New Jersey, U.S.A., April 1, 1918. Lust’s introduction is reprinted here in its entirety to show the purpose of the directory and the status of the profession in the early 1900s: 

Introduction To the Naturopathic Profession, the Professors of Natural Healing in all its branches, the Professors of Scientific Diet, Hydrotherapy, Heliotherapy, Electrotherapy, Neuropathy, Osteopathy, Chiropractic, Naprapathy, Magnetopathy, Phytotherapy, Exercise, Swedish Movements, Curative Gymnastics, Physical and Mental Culture, Balneopathy, and all forms of Drugless Healing, the Faculties of all Drugless Colleges, Institutions, Schools, and all Professors of Hygiene and Sanitation; Manufacturers of Naturopathic Supplies; Publishers of Health Literature, and Natural Healing Societies, GREETINGS: I have the honor to present to your consideration and goodwill, this Volume, No. 1, Year 1918–1919, of the Universal Naturopathic Directory, Year Book of Drugless Healing, and Buyers’ Guide. For twenty-two years past, the need of a directory for Drugless Therapy has been felt. The medical world is in a condition of intense evolution at the present time. It is evolving from the Drugging School of Therapy to the Drugless School. People by the million have lost confidence in the virtues of Allopathy and are turning with joyful confidence to the Professions of Natural Healing until it has been estimated that there are at least forty thousand practitioners of Naturopathic healing in the United States.The motto that IN UNITY THERE IS STRENGTH is the foundation of the present enterprise.

Hitherto, the drugless profession has lacked that prestige in the eyes of the public, which comes from the continuous existence of a big institution, duly organized and wielding the immense authority which is derived no less from organization and history than from the virtues of the principles that are held and practiced by such institutions. The public at large instantaneously respects an institution that is thoroughly organized and has its root earthed in history. The time has fully arrived when the drugless profession should no longer exist in the form of isolated units, not knowing one another and caring but little for such knowledge. Our profession has been, as it were, as sheep without a shepherd, but the various individuals that constitute this movement so pregnant with benefits to humanity, are now collected for the first time into a Directory and Year-Book of Drugless Healing, which alone will give immense weight and dignity to the standing of the individuals mentioned therein.Not only will the book add to the prestige of the practitioner in the eyes of his patients, but when the scattered members of our profession in every State desire to obtain legislative action on behalf of their profession and themselves, the appeal of such a work as our directory will, in the eyes of legislators, gain for them a much more respectful hearing than could otherwise be obtained. Now, for the first time, the drugless practitioner finds himself one of a vast army of professional men and women who are employing the most healthful forces of nature to rejuvenate and regenerate the world. But the book itself throws a powerful light upon every phase of drugless healing and annihilates time and distance in investigating WHO IS WHO in the realm of Drugless Therapy. A most sincere effort has been made to obtain the name and address of every adherent of the Rational School of Medicine who practices his profession within the United States, Canada and the British Isles. It is impossible at this stage of Naturopathic history, which is still largely in the making, to obtain the name and address of every such practitioner. There were some who, even when appealed to, refused to respond to our invitation, not understanding the object of our work. Many of even the most intelligent members have refused to advertise their professional cards in our pages. But we can only attribute these drawbacks to the fact that every new institution that has suddenly dawned upon human intelligence will find that a certain proportion of people who do not understand the nature of the enterprise because the brain cells that would appreciate the benefits that are sought to be conferred upon them, are undeveloped, but a goodly proportion of our Naturopaths have gladly responded to the invitation to advertise their specialty in our columns. These, of course, constitute the brightest and most successful of our practitioners and their examples in this respect should be followed by every practitioner whose card does not appear in this book.We take it for granted that every one of the forty thousand practitioners of Naturopathy is in favor of the enterprise represented by this Directory. This work is a tool of his trade and not to possess this book is a serious handicap in the race for success. Here will be found an Index of by far the larger number of Naturopaths in the country arranged in Alphabetic, Geographic and Naturopathic sections. Besides this, there is a classified Buyers’ Guide that gives immediate information regarding where you can find special supplies, or a certain apparatus, or a certain book or magazine, its name, and where it is published. The list of Institutions with the curriculum of each will be found exceedingly useful. Natural healing, that has drifted so long, and, by reason of a lack of organization, has been made for so many years the football of official medicine, to be kicked by any one who thought fit to do so, has now arrived at such a pitch of power that it has shaken the old system of bureaucratic medicine to its foundations. The

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

professors of the irrational theories of life, health and disease, that are looking for victims to be inoculated with dangerous drugs and animalized vaccines and serums, have begun to fear the growth of this young giant of medical healing that demands medical freedom, social justice and equal rights for the new healing system that exists alone for the betterment and uplifting of humanity. I want every Professor of Drugless Therapy to become my friend and co-worker in the great cause to which we are committed, and those whose names are not recorded in this book should send them to me without delay. It will be of far greater interest and value to themselves to have their professional card included amongst those who advertise with us than the few dollars that such advertisement costs. It will be noted that there are quite a number of Drugless Healers belonging to foreign countries (particularly those of the Western Hemisphere) represented in this Directory. The profession of medicine is not confined to any race, country, clime or religion. It is a universal profession and demands universal recognition. It will be a great honor to the Directory, as well as to the Naturopathic profession at large to have every Naturopathic practitioner, from the Arctic Circle to the furthest limits of Patagonia, represented in the pages of this immense and most helpful work. I expect that the Directory for the year 1920 will be larger and even more important than the present Directory and that it will contain the names of thousands of practitioners that are not included in the present work. The publication of this Directory will aid in abolishing whatever evils of sectarianism, narrow-mindedness and lack of loyalty to the cause to which we are devoted, that may exist. That it will promote a fraternal spirit among all exponents of natural healing, and create an increase of their prestige and power to resist the encroachments of official medicine on their constitutional rights of liberty and the pursuit of happiness, by favorably influencing Legislators, Law courts, City Councils and Boards of Health everywhere, is the sincere belief of the editor and publisher. Having introduced the volume, Lust leads off with his article entitled “The principles, aim, and program of the nature cure system.” Again, this relatively brief article is reproduced here in its entirety so that one can see the merging of influences: 

The Principles, Aim, and Program of the Nature Cure System Since the earliest ages, Medical Science has been of all sciences the most unscientific. Its professors, with few exceptions, have sought to cure disease by the magic of pills and potions and poisons that attacked the ailment with the idea of suppressing the symptoms instead of attacking the real cause of the ailment. Medical science has always believed in the superstition that the use of chemical substances which are harmful and destructive to human life will prove an efficient substitute for the violation of laws, and in this way encourages the belief that a man may go the limit in self indulgences that weaken and destroy his physical system, and then hope to be absolved from his physical ailments by swallowing a few pills, or submitting to an injection of a serum or vaccine, that are supposed to act as vicarious redeemers of the physical organism and counteract life-long practices that are poisonous and wholly destructive to the patient’s well-being. From the earliest ages to the present time, the priests of medicine have discovered that it is ten times easier to obtain ten dollars from a man by acting upon his superstition, than it is to extract one dollar from him, by appealing to reason and common sense. Having this key to a gold mine within their grasp, we find official medicine

indulging at all times in the most blatant, outrageous, freakish and unscientific methods of curing disease, because the methods were in harmony with the medical prestige of the physician. Away back in pre-historic times, disease was regarded as a demon to be exorcized from its victim, and the medicine man of his tribe belabored the body of his patient with a bag in which rattled bones and feathers, and no doubt in extreme cases the tremendous faith in this process of cure that was engendered in the mind of the patient really cured some ailments for which mental science and not the bag of bones and feathers should be given credit. Coming down to the middle ages, the Witches’ Broth—one ingredient of which was the blood of a child murderer drawn in the dark of the moon—was sworn to, by official medicine, as a remedy for every disease. In a later period, the “docteur a la mode,” between his taking pinches of snuff from a gold snuff box, would order the patient bled as a remedy for what he denominated spirits, vapors, megrims, or miasms. Following this pseudo-scientific diagnosis and method of cure, came the drugging phase in which symptoms of disease were unmercifully attacked by all kinds of drugs, alkalis, acids and poisons which were supposed, that by suffocating the symptoms of disease, by smothering their destructive energy, to thus enhance the vitality of the individual. All these cures have had their inception, their period of extensive application, and their certain desuetude. The contemporary fashion of healing disease is that of serums, inoculations and vaccines, which, instead of being an improvement on the fake medicines of former ages are of no value in the cure of disease, but on the contrary introduce lesions into the human body of the most distressing and deadly import. The policy of expediency is at the basis of medical drug healing. It is along the lines of self-indulgence, indifference, ignorance and lack of self-control that drug medicine lives, moves and has its being. The sleeping swineries of mankind are wholly exploited by a system of medical treatment, founded on poisonous and revolting products, whose chemical composition and whose mode of attacking disease, are equally unknown to their originators, and this is called “Scientific medicine.” Like the alchemist of old who circulated the false belief that he could transmute the baser metals into gold, in like manner the vivisector claims that he can coin the agony of animals into cures for human disease. He insists on cursing animals that he may bless mankind with such curses. To understand how revolting these products are, let us just refer to the vaccine matter which is supposed to be an efficient preventive of smallpox. Who would be fool enough to swallow the putrid pus and corruption scraped from the foulest sores of smallpox that has been implanted in the body of a calf? Even if any one would be fool enough to drink so atrocious a substance, its danger might be neutralized by the digestive juices of the intestinal tract. But it is a far greater danger to the organism when inoculated into the blood and tissues direct, where no digestive substances can possibly neutralize its poison.The natural system for curing disease is based on a return to nature in regulating the diet, breathing, exercising, bathing and the employment of various forces to eliminate the poisonous products in the system, and so raise the vitality of the patient to a proper standard of health. Official medicine has in all ages simply attacked the symptoms of disease without paying any attention to the causes thereof, but natural healing is concerned far more with removing the causes of disease, than merely curing its symptoms. This is the glory of this new school of medicine that it cures by removing the causes of the ailment, and is the only rational method of practicing medicine.

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Philosophy of Natural Medicine

It begins its cures by avoiding the uses of drugs and hence is styled the system of drugless healing. It came first into vogue in Germany and its most famous exponents in that country were Priessnitz, Schroth, Kuhne, Kneipp, Rickli, Lahmann, Just, Ehret, Engelhardt, and others. In Sweden, Ling and others developed various systems of mechano-therapy and curative gymnastics. In America, Palmer invented Chiropractic; McCormick, Ophthalmology. Still originated Osteopathy; Weltmer, suggestive Therapeutics. Lindlahr combined the essentials of various natural methods, while Kellogg, Tilden, Schultz, Trall, Lust, Lahn, Arnold, Struch, Havard, Davis, Jackson, Walters, Deininger, Tyrell, Collins and others, have each of them spent a lifetime in studying and putting into practice the best ideas of drugless healing and have greatly enlarged and enriched the new school of medicine. 

Life Maltreated by Allopathy The prime object of natural healing is to give the principle of life the line of least resistance, that it may enable man to possess the most abundant health. 

What Is Life? The finite mind of man fails to comprehend the nature of this mysterious principle. The philosopher says “Life is the sum of the forces that resist death,” but that definition only increases its obscurity. Life is a most precious endowment of protoplasm, of the various combinations of oxygen, hydrogen, carbon and nitrogen, and other purely mineral substances in forming organic tissues. As Othello says, referring to Desdemona’s life, which he compares to the light of a candle— “If I quench thee thou flaming minister, I can thy former light restore Should I repent me; but once put out THY light, I know not whence is that Promethean heat That can thy light relume.” The spark of life flickers in the sockets of millions and is about to go out. What system of medicine will most surely restore that flickering spark to a steady, burning flame? Will [it be] the system that employs poisonous vaccines, serums and inoculations, whose medical value has to be supported by the most mendacious statements, and whose practitioners are far more intent on their emoluments and fame, than they are in the practice of humanity? The Allopathic system, which includes nine tenths of all medical practitioners, is known by its fruits, but it is an appalling fact that infant mortality, insanity, heart disease, arteriosclerosis, cancer, debility, impoverished constitutions, degeneracy, idiocy and inefficiency have enormously increased, particularly during the last twenty-five years, that is, during the regime of inoculations, serums and vaccines. Naturopathy, on the other hand, so far as it has been developed, and so far as official medicine will allow it to act, leaves no such trail of disease, disaster and death behind it. Natural healing is emancipation from medical superstition, ignorance and tyranny. It is the true Elixir of Life. The Allopaths have endeavored to cure sick humanity on the basis of the highly erroneous idea that man can change the laws of nature that govern our being, and cure the cause of disease by simply ignoring it. To cure disease by poisoning its symptoms is medical manslaughter. Dr. Schwenninger of Germany says: “We are suffering under the curse of the past mistakes of our profession. For thousands of years medical doctors have been educating the public into the false belief that poisonous drugs can give health. This belief has become in the public

mind such a deep-seated superstition, that those of us who know better and who would like to adopt more sensible, natural methods of cure, can do so only at the peril of losing practice and reputation. “The average medical man is at his best but a devoted bigot to this vain school-craft, which we call the Medical Art and which alone in this age of science has made no perceptible progress since the days of its earliest teachers. They call it recognized science! Recognized ignorance! The science of to-day is the ignorance of to-morrow. Every year some bold guess lights up as truth to which but the year before the schoolmen of science were as blind as moles.” And Dr. O.W. Holmes, Professor of Anatomy in Harvard University, states: “The disgrace of medicine has been that colossal system of self-deception, in obedience to which mines have been emptied of their cankering minerals, entrails of animals taxed for their impurities, the poison bags of reptiles drained of their venom, and all the inconceivable abominations thus obtained thrust down the throats of human beings, suffering from some fault of organization, nourishment, or vital stimulation.” And these misguided drug doctors are not only not ashamed of their work, but they have induced subservient legislators to pass laws that perpetuate the age-long scandal of allopathic importance, and the degenerative influence of the poisons, and to actually make it a crime on the part of nature doctors to cure a man of his ailment. The brazen effrontery of these medical despots has no limits. They boast of making the State legislators their catspaw in arresting, fining and imprisoning the professors of natural healing for saving human life. Legislators have no right to sit in judgment over the claims of rival schools of healing. They see tens of thousands of sick people go down to their graves by being denied the cures that the employers of nature’s forces alone can give them. It is their business to provide for the various schools of medicine a fair field and no favor. A citizen has an inalienable right to liberty in the pursuit of happiness. Yet the real saviors of mankind are persecuted by the medical oligarchy which is responsible for compulsory vaccination, compulsory medical inspection of public school children, and the demands for State and Federal departments of health, all for the ostensible good of the people, but in reality for the gain of the Medical Trust. 

The Naturopaths The Naturopaths are desirous of freedom for all schools of medicine. They are responsible practitioners who are willing to be examined by an impartial council, appointed by and acting for the State, who will testify to the life and character of every drugless physician before he is entitled to practice medicine. Not one invidious discrimination should be made between the different schools of medicine. The state should see to it that each school should have a full opportunity to do its best for the up-lifting of its citizens. 

The Program of Naturopathic Cure 1. ELIMINATION OF EVIL HABITS, or the weeds of life, such as overeating, alcoholic drinks, drugs, the use of tea, coffee and cocoa that contain poisons, meat eating, improper hours of living, waste of vital forces, lowered vitality, sexual and social aberrations, worry, etc. 2. CORRECTIVE HABITS. Correct breathing, correct exercise, right mental attitude. Moderation in the pursuit of health and wealth. 3. NEW PRINCIPLES OF LIVING. Proper fasting, selection of food, hydropathy, light and air baths, mud baths, osteopathy, chiropractic and other forms of mechano-therapy, mineral salts obtained in organic form, electropathy, heliopathy, steam or Turkish baths, sitz baths, etc.

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

Natural healing is the most desirable factor in the regeneration of the race. It is a return to nature in methods of living and treatment. It makes use of the elementary forces of nature, of chemical selection of foods that will constitute a correct medical dietary. The diet of civilized man is devitalized, is poor in essential organic salts. The fact that foods are cooked in so many ways and are salted, spiced, sweetened and otherwise made attractive to the palate, induces people to over-eat, and over eating does more harm than under feeding. High protein food and lazy habits are the cause of cancer, Bright’s disease, rheumatism and the poisons of auto-intoxication. There is really but one healing force in existence and that is Nature herself, which means the inherent restorative power of the organism to overcome disease. Now the question is, can this power be appropriated and guided more readily by extrinsic or intrinsic methods? That is to say, is it more amenable to combat disease by irritating drugs, vaccines and serums employed by superstitious moderns, or by the bland intrinsic congenial forces of Natural Therapeutics, that are employed by this new school of medicine, that is Naturopathy, which is the only orthodox school of medicine? Are not these natural forces much more orthodox than the artificial resources of the druggist? The practical application of these natural agencies, duly suited to the individual case, are true signs that the art of healing has been elaborated by the aid of absolutely harmless, congenial treatments, under whose ministration the death rate is but five per cent of persons treated as compared with fifty per cent under the present allopathic methods. 

The Germanic Influence The philosophic origins of naturopathy were Germanic. The most significant influences, except those of Russell Trall, the osteopathic concepts of A.T. Still (at this time, strictly the correction of spinal lesions by adjustment), and the chiropractic principles of D. D. Palmer, were originally Germanic. (This was well established in the January 1902 editorial in Water Cure Monthly.) The specific influences on which Lust drew for his work, in order of their chronologic contributions to the system of naturopathy, are the following: 1. Vincent Preissnitz (1799–1851) 2. Johann Schroth (1798–1856) 3. Father Sebastian Kneipp (1821–1897) 4. Arnold Rickli (1823–1926) 5. Louis Kuhne (c. 1823–1907) 6. Henry Lahman (no dates known) 7. F. E. Bilz (1823–1903) 8. Adolph Just (1859–1939). Also of note were Theodor Hahn and T. Meltzer, who, in the 1860s, were well known for their work in the movement called, in German, Naturatz or “naturism.” In photographs accompanying his article “The principles, aim and program of the nature cure system,” Lust described each of these thinkers as follows: 1. VINCENT PREISSNITZ, of Graefenberg, Silesia. Founder of Hydropathy. Born October 4, 1799. A pioneer Naturopath, prosecuted by the medical authorities of his day, and convicted of using witchcraft, because he cured his patients by the use of water, air, diet and exercise. He took his patients back to Nature—to the woods, the streams, the open fieldstreated them with Nature’s own forces and fed them on natural foods. His fame spread over the whole of Europe, and even to America. His cured patients were numbered by the thousands. The Preissnitz compress or bandage is in the medical literature. Preissnitz is no more, but his spirit lives in every true Naturopath.

2. JOHANN SCHROTH, a layperson, not described in Lust’s directory but often talked of in later works and prominently mentioned for his curative theories in Bilz’s master work, The Natural Method of Healing. Schroth smashed his right knee in an accident with a horse and it remained stiff in spite of repeated medical treatment. At last, a priest told Schroth that Preissnitz’s methods might help, and Schroth decided to give them a try. In order to avoid frequent changing of the packs that were directed by Preissnitz, he placed several packs on top of one another, wrapping the whole portion with a woolen cloth. He left this pack on the injured knee for several hours and produced a moist heat which he theorized to cause the poisonous toxins to dissolve and be swept away. These packs are still used as part of the “Schroth cure” and have reportedly become famous for their blood-cleansing effect. (From an article in the March 1937 Naturopath and Herald of Health by Dr. T.M. Schippel.) As noted by Bilz, the Schroth cure, called by Bilz “the regenerative treatment,” was developed for treatment of chronic diseases through the use of an extreme diet following total fasting by withdrawing of all food and drink and then the use of totally dry grain products and the eventual reintroduction of fluids. 3. FATHER SEBASTIAN KNEIPP, of course, is much described and the photos include one of Kneipp lecturing to the multitudes at Wandelhale at Woerishofen, attending Pope Leo XIII in 1893, noting this is the only consultation on health care matters that Kneipp ever consented to outside of Woerishofen, though many famous and aristocratic individuals desired his counsel, and a picture of Kneipp with the Archdukes Joseph and Francis Ferdinand of Austria walking barefoot in new-fallen snow for purposes of hardening the constitution. It was noted that the older Archduke was cured by Kneipp of Bright’s disease in 1892, and it noted that the Archduke Joseph, in appreciation of this cure, donated a public park in the town of Woerishofenat a cost of $150,000 florens. The Archduke Francis Ferdinand, the son of Archduke Joseph, was the individual whose murder precipitated World War I. There is a further picture of Kneipp surrounded consultation to numerous patients. 4. ARNOLD RICKLI, founder of the light and light and aircures (atmospheric cure). Dr. Rickli was one of the foremost exponents of natural living and healing. In 1848, he established at Veldes, Krain, Austria, the first institution of light and air cure or as it was called in Europe the “atmospheric cure.” In a limited way (rather very late) his ideas have been adopted by the medical profession in America for the cure of consumption. He was an ardent disciple of the vegetarian diet and exemplified the principles of natural living in his own life. The enclosed photo shows him at the age of 97, when he was still active and healthy. He has since passed on, but his work still lives as a testimonial of his untiring efforts. He was the founder and for over 50 years the President of the National Austrian Vegetarian Association. 5. LOUIS KUHNE wrote, in 1891, The New Science of Healing, the greatest work of basic principles in natural healing. In the tradition of Natural Healing and prevention, Kuhne has been described as one who “… advocated sun, steam baths, a vegetarian diet, and whole-wheat bread … in these relatively early days.” His renowned work constitutes the only true scientific philosophy for the application of all Drugless Methods. He was the first to give to the world the comprehensible idea of pathology and the first to proclaim the doctrine of the “unity of cure.” His book Facial Expression gives the means of diagnosing a patient’s pathological condition and determining the amount and location of the systemic encumbrance. He is the founder and first Master of Naturopathy.

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6. DR. H. LAHMAN. When the University of Leipzig expelled H. Lahman for his spreading medical sedition among the students, it added a staunch advocate to natural healing. Dr. Lahman finished his medical education in Switzerland and returned to Germany to refute in practice the false ideas of medical science. He later founded the largest Nature Cure institution in the world at Weisser Hirsch, near Dresden, Saxony. He was a strong believer in the “Light and Air” cure and constructed the first appliances for the administration of electric light treatment and baths. He was the author of several books on Diet, Nature Cure and Heliotherapy. As noted in Other Healers, Other Cures: “Heinrich Lahmann came along to stress no salt on foods and no water with meals …” His works on diet are authoritative and his “nutritive salts theory” forms the basis of rational dietetic treatment. This work has but recently come to light in America, and progressive dietitians are forsaking their old, wornout, high protein, chemical and caloric theories for the “organic salts theory.” Carque, Lindlahr, McCann, and other wide awake food scientists have adopted it as a basis for their work. Dr. Lahman was a medical nihilist. He denounced medicine as unscientific and entirely experimental in its practice and lived to prove the saneness of his ideas as evidenced by his thousands of cured patients. 7. PROFESSOR F.E. BILZ. That real physicians are born, not made, is well illustrated in the case of Dr. Bilz, who achieved his first success in healing as a lay practitioner. As a mark of gratitude, a wealthy patient presented him with land and a castle in which to found a Nature Cure anitarium.… The Bilz institution at Dresden-Rdebeul, Germany, became world renowned and was long considered the center of the Nature Cure movement. Professor Bilz is the author of the first Naturopathic encyclopedia, The Natural Method of Healing, which has been translated into a dozen languages, and in German alone has run into 150 editions. He has written many works on Nature Cure and Natural Life, among them being The Future State, in which he predicted the present World War, and advocated a federation of nations as the only logical solution of international problems. 8. ADOLPH JUST, famous author of Return to Nature and founder of original “Yungborn” in Germany. Both Adolph Just’s Return to Nature and Louis Kuhne’s The Natural Science of Healing were translated into English by Lust and released through his publication house. 

The Convergence With American Influences The Universal Naturopathic Directory was truly eclectic in its compilation and composition. Besides the Lust articles, the volume included “How I became acquainted with nature cure” by Henry Lindlahr, MD, ND (which was reproduced in large part in the introduction to volume 1 of Lindlahr15); “The nature cure” by Carl Strueh, MD, ND; “Naturopathy” by Harry E. Brook, ND; “The present position of naturopathy and allied therapeutic measures in the British Isles” by Allen Pattreiouex, ND; “Why all drugless methods?” by Per Nelson; and “Efficiency in drugless healing” by Edward Earle Purinton (a reprint of the 1917 publication, referred to earlier, which was composed of a series of articles published in The Herald of Health and Naturopath between August 1914 and February 1916). The volume also contained Louis Kuhne’s “Neo-naturopathy (the new science of healing),” in the first publication of the translation by Lust, and articles on electrotherapy, neuropathy, dietology, chiropractic, mechanotherapy, osteopathy, phytotherapy, apyrtropher, physical culture, optometry, hydrotherapy, orthopedics, pathology, natural healing and living, astroscopy, phrenology, and physiology—all of

which were specially commissioned for the directory from practitioners and authors considered expert in these subjects. Also included was a national directory of drugless physicians in alphabetical order, geographically arranged and itemized by profession; biographic notes on American contributors of note; the naturopathic book catalog; a guide to natural healing and natural life books and periodicals; a classified list of medical works; a series of book reviews; a buyer’s guide for naturopathic supplies; and, in addition to extensive indexes, a “parting word” by Lust. The volume contained numerous advertisements for naturopathic schools, sanitariums, and individual practices, and it closed with the following note: This, then, completes Volume 1 of the Naturopathic Directory, Drugless Yearbook and Buyer’s Guide for the years 1918 and 1919. Into it, has been placed the conscientious labor of many willing hearts, hands and minds. It is their contribution to the noble cause of natural healing. It will stand as a monument to their endeavors, as well as a memorial to the great souls, the fathers of natural healing, who have passed on. Let this, then, herald a new era—the era wherein man shall recognize the omniscience of Nature, and shall profit through conforming to her laws. In the biographic sections, it is apparent that Lust owed a great deal of the feeling of camaraderie in the nature cure movement to some varied American practitioners. The most prominent of these had their biographic sections contained in the 1918 directory. Two of them deserve specific note and attention: Palmer and Still. Lust met A. T. Still in 1915 in Kirksville, Missouri, shortly before Still’s death. From their meetings, Lust noted later in the Naturopath and Herald of Health (June 1937) that Still believed that osteopathy by “compromising with medicine is doomed as the school that could have incorporated all the natural and biological healing arts.” Lust wanted naturopathy to fill this void. Lust also had a lengthy acquaintance with B. J. Palmer (the son of D. D. Palmer, the founder of chiropractic), who, following in his father’s footsteps, put Davenport, Iowa, and the Palmer Chiropractic College on the map. Lust also became connected with Henry Lindlahr, MD, ND, of Chicago (as noted in the autobiographical sketch contained in the directory16 and reprinted in volume 1 of Lindlahr15). Lindlahr was a rising businessman in Chicago with all the bad habits of the “gay nineties” era. In his 30s, he became chronically ill. He had gone to the orthodox practitioners of his day and received no relief. Then he was exposed to Schroth’s works, and in following them began to feel somewhat better. Subsequently, he liquidated all his assets and went to a German sanitarium to be cured and to learn nature cure. He returned to Chicago and enrolled in the Homeopathic/Eclectic College of Illinois. In 1903 he opened a sanitarium, which included a residential sanitarium, located in Elmhurst, Illinois; a “transient” clinic (office) on State Street in Chicago; and “Lindlahr’s Health Food Store.” Shortly thereafter, he founded the Lindlahr College of Natural Therapeutics, which included hospital internships at the sanitarium. The institution became one of the leading naturopathic colleges of the day. In 1908 he began to publish Nature Cure Magazine and began publishing his series of Philosophy of Natural Therapeutics, with volume 1 (“Philosophy”) in 1918. This was followed by volume 2 (“Practice”) in 1919; volume 3 (“Dietetics”; republished with revisions as originally published in 1914); and, in 1923, volume 6 (“Iridiagnosis”). The intended volumes 4 and 5 were in production at the time of Lindlahr’s death in 1927. As described in Other Healers, Other Cures17:

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

Henry Lindlahr, another American, is remembered for his conviction that disease did not represent an invasion of molecules, but the body’s way of healing something. In other words, he viewed symptoms as a positive physiological response—proof that the body is fighting whatever’s wrong. Accordingly, a fever is a “healthy” sign and one should be let alone, unless it is dangerously high, of course. The effect of all these gentlemen on the development of naturopathy in America, under Lust’s guidance, was profound. From these beginnings, the naturopathic movement gathered strength and continued to grow through the 1920s and 1930s, having a major effect on natural healing and natural lifestyles in the United States. Along the way, Lust was greatly influenced by the writings of John H. Tilden, MD (largely published between 1915 and 1925). Tilden was originally a practicing physician in Denver who became disenchanted with orthodox medicine and began to rely heavily on dietetics and nutrition, formulating his theories of “auto-intoxication” (the effect of fecal matter remaining too long in the digestive process) and “toxemia.” Lust was also greatly influenced by Elmer Lee, MD, who became a practicing naturopath around 1910 and whose movement was called the “hygienic system,” following the earlier works of Russell Trall. Lee published Health Culture for many years. In addition to John Tilden, MD, and Elmer Lee, MD, another medical doctor, John Harvey Kellogg, MD, who turned to more nutritionally based natural healing concepts, was greatly respected by Lust. Kellogg was renowned through his connection with the Battle Creek Sanitarium. The sanitarium itself was originally founded in the 1860s as a Seventh-Day Adventist institution designed to perpetuate the Grahamite philosophies of Sylvester Graham and William Alcott. The sanitarium was on the verge of being closed, however, because of economic failure, when, in 1876, Kellogg, a new and more dynamic physician-in-chief, was appointed. Kellogg, born in 1852, was a “sickly child” who, at the age of 14, ran across the works of Graham and converted to vegetarianism. At the age of 20, he studied for a term at Trall’s Hygio-Therapeutic College and then earned a medical degree at New York’s Bellevue Medical School. He maintained an affiliation with the regular schools of medicine during his lifetime, due more to his practice of surgery than his beliefs in the area of health care.4 Kellogg designated his concepts, which were basically the hygienic system of healthful living, “biologic living.” Principally, Kellogg defended vegetarianism, attacked sexual misconduct and the evils of alcohol, and was a prolific writer throughout the late 19th century and early 20th century. He produced a popular periodical, Good Health, which continued in existence until 1955. When Kellogg died in 1943 at the age of 91, he had had more than 300,000 patients through the Battle Creek Sanitarium (which he had renamed from the Western Health Reform Institute shortly after his appointment in 1876), including many celebrities, and the “San” became nationally well known. Kellogg, along with Tilden and Elie Metchnikoff (director of the prestigious Pasteur Institute and winner of the 1908 Nobel Prize for a contribution to immunology), wrote prolifically on the theory of auto-intoxication. Kellogg, in particular, felt that humans, in the process of digesting meat, produced various intestinal self-poisons that contributed to auto-intoxication. As a result, Kellogg became a near fanatic on the subject of helping humans return to a more healthy, natural state by returning to the naturally designed usage of the colon. He felt that the average modern colon was devitalized by the combination of sedentary living, the custom of sitting rather than squatting to defecate, and the modern

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civilized habit of ignoring “nature’s call” out of an undue concern for politeness. Further, Kellogg concentrated on the fact that the modern diet had insufficient bulk and roughage to stimulate the bowels to proper action. Kellogg was also extremely interested in hydrotherapy. In the 1890s he established a laboratory at the San to study the clinical applications of hydrotherapy. This led, in 1902, to his writing Rational Hydrotherapy. The preface espoused a philosophy of drugless healing that came to be one of the bases of the hydrotherapy school of medical thought in America. Tilden, as mentioned, was of a similar mind. He must have been to have provided natural healthcare literature with his 200-plus-page dissertation entitled “Constipation,” with a chapter devoted to the evils of not responding when nature called. This belief in the “evils” drawing away from the natural condition of the colon was extremely important to Kellogg’s work.4 Because of Lust’s interest, Kellogg’s The New Dietetics (1921) became one of the bibles of naturopathic literature.18 Lust was also influenced by the works of Sidney Weltmer, the father of “suggestive therapeutics.” The theory behind Professor Weltmer’s work was that whether it was the mind or the body that first lost its grip on health, the two were inseparably related. When the problem originated in the body, the mind nonetheless lost its ability and desire to overcome the disease because the patient “felt sick” and consequently slid further into the diseased state. Alternatively, if the mind first lost its ability and desire to “be healthy” and some physical infirmity followed, the patient was susceptible to being overcome by disease. Weltmer’s work dealt specifically with the psychological process of desiring to be healthy. Lust enthusiastically backed Weltmer’s work and had him appear on the programs at various annual conventions of the American Naturopathic Association (which commenced after its founding in 1919). Lust was also personal friends with and a deep admirer of Bernarr MacFadden.19 MacFadden was the founder of the “physical culture” school of health and healing, also known as “physcultopathy.” This school of healing gave birth across the country to gymnasiums at which exercise programs, designed to allow the individual man or woman to maintain the most perfect state of health and human condition possible, were developed and taught.4 Other Healers, Other Cures described it as follows15: The next Naturopathic star, after Kellogg, was Bernarr MacFadden, the physical culturist who built a magazine-publishing empire (his first magazine was Physical Culture founded in 1898). MacFadden proselytizes for exercise and fresh vegetables, hardly eccentric notions. But his flamboyant efforts to publicize them and his occasional crack-pot ideas (like freezing the unemployed, then thawing them out when the Depression was over) alienated many people. Still, he was his own best advertisement. He fathered nine children by four wives and was parachuting from planes in his 80s. One of MacFadden’s admirers was that arch-foe of the medical profession, George Bernard Shaw, the longevous eccentric in his own right. Lust was also interested in, and helped publicize, “zone therapy,” originated by Joe Shelby Riley, DC, a chiropractor based in Washington, DC, and one of the early practitioners of “broad chiropractic.” Zone therapy was an early forerunner of acupressure as it related “pressures and manipulations of the fingers and tongue, and percussion on the spinal column, according to the relation of the fingers to certain zones of the body.”17 Several other American drugless healers contributed to a broad range of “-opathies” that Lust merged into his growing view of naturopathy as the eclectic compilation of methods of natural healing. The

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Philosophy of Natural Medicine

Universal Directory also contained a complete list of osteopaths and chiropractors as drugless healers within the realm of Lust’s view of naturopathic theory. His other significant compatriots at the time of the publication of the directory were Carl Stueh, described by Lust as “one of the first medical men in this country who gave up medicine and operation for natural healing”; F. W. Collins, MD, DO, DC, an early graduate of the American School of Naturopathy (1907) who went on to graduate from the New Jersey College of Osteopathy (1909) and the Palmer School of Chiropractic (1912); another “broad chiropractor,” Anthony Matijaca, MD, ND, DO, the naturopathic resident expert in electrotherapy and an associate editor of the Herald and Health Naturopath (the inverted name of the Lust journal at the time of the directory); and Carl Schultz, ND, DO, MD, president and general manager of the Naturopathic Institute and Sanatorium of California, essentially the second school in the country to pursue the education of physicians under the name of “naturopathy.” In Inner Hygiene: Constipation and the Pursuit of Health in Modern Society, Whorton20 offered his first assessments of the work of Lust as it related to the emergence of naturopathy in the early 20th century: Most of the drugless clan also identified themselves as practitioners of naturopathy, a system of practice that grew out of hydropathy, as well as German water-cure and nature-cure traditions. Organized in the late 1890s under the leadership of German immigrant Benedict Lust, naturopathy sought to cure the full scope of human ills with natural agents (herbs, water, air, sunlight, electricity, massage, and others), agents that supported and stimulated the body’s own healing mechanisms. In his extensive assessments of Lust’s work and writings in Nature Cures: The History of Alternative Medicine in America, Whorton21 attempted to put the philosophic development of naturopathy in a reasonable historical context: However much a dreamer Lust was in some respects, he was an insightful realist in others. He was correct in believing that simply giving nature support as it ran its course was the best one could do with many diseases in his day. He was correct in seeing self-abuse as the source of much physical, and emotional, suffering and attacked it with an ardor that MDs could not bring to the task until nearly a century later. Recent medical lamentations over the evils of smoking, sexual promiscuity, and other risky behaviors adopted in the thoughtless chase after pleasure have nothing on Lust’s jeremiads … Lust was right in reprimanding allopaths for focusing so strongly on disease as to lose sight of the importance of promoting health. He was right in appreciating the need to “individualize” the treatment of each patient—and in seeing patient self-responsibility as part of that individualization. 

EARLY-20TH-CENTURY MEDICINE The Metamorphosis of Orthodox Medicine Naturopathy’s formative years, and in some respects its halcyon days, were from 1900 to 1917. In many jurisdictions, modern licensing laws were not yet in effect, so varied schools of healing were openly practiced. By 1920, however, the American world of medicine had undergone a sharp transition, culminating in four decades of change. A look at the structure of early medical care in the United States is instructive, even as practiced and dominated by the orthodox school, when noting the changes that occurred between 1875 and 1920. In 1875 the following was descriptive of American medical practice: • The practice, even in urban areas, sent the doctor to the patient; the “house call” was the norm. • There was little modern licensing regulation.

• H  ospitals were charitable institutions where persons too poor to otherwise receive health care were usually sent when ill. • The AMA, although formed in 1846 and generally representative of the professional goals of the regular or orthodox school of medicine, had scarcely begun to make any political inroads at all. • Medical schools required little or no college education for entrance and were largely apprenticeship based and proprietary in nature, having changed little throughout the century. • Although some doctors had begun to specialize, to do so was far from the norm. The major recognized specialties were surgery, obstetrics, and gynecology. • Many different types of doctors existed, and society’s reaction to the profession neither recognized specific expertise nor necessarily rewarded professionals in medical practice well. • Although the orthodox school made up roughly 80% of professional medical practitioners, the homeopaths and the eclectics were visible and respected in their own communities for their abilities and expertise, and much of the public relied on other “irregular” practitioners. By comparison, in 1920, a total metamorphosis of the medical profession had occurred: • By 1920, practices had become office oriented and clinic oriented. • Modern licensing principles had become fully developed, and physicians and surgeons were licensed in all jurisdictions. Most other healthcare providers had some licensing restrictions placed on them, if they were recognized at all. • Due largely to the introduction into surgery of the practice of antiseptic techniques and aseptic procedures and a correspondent decline in operative mortality, institutional care in the hospital became increasingly accepted. Also, clinical pathology and diagnostic laboratory procedures had become well developed, and the hospital had become a major training and clinical research facility that was generally more acceptable to the patient. • The AMA was approaching the peak of its political power, having exercised, through its Council on Medical Education and its Council of Pharmacy and Chemistry, major effects on medical schools and the pharmaceutical industry. • The transition to research- and education-based medical schools, instead of practitioner apprenticeships and proprietary education, had become complete. All recognized medical schools had a 4-year curriculum, with an undergraduate degree or substantial undergraduate study required as a prerequisite. In addition, most schools, in conjunction with most licensing statutes, required a year’s internship. • Specialization was becoming well developed, and the number of specialty groups had increased considerably. This would continue throughout the 1930s and into the early 1940s. • Professional authority and autonomy had undergone a substantial transition, and the allopathic physician was now recognized as a medical expert. • By 1922, the last eclectic school was on the verge of closure, and in the early 1930s, the last of the homeopathic schools in the United States was also on the verge of closure. The influence of these sects on orthodox medicine had dwindled to almost nothing. Naturopaths and other alternative healthcare practitioners had adopted the areas of expertise previously considered the territory of homeopaths and eclectics. 

The Halcyon Years of Naturopathy In 1924 Morris Fishbein succeeded George Simmons as editor of the Journal of the American Medical Association (JAMA). Fishbein had

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

joined the editorial staff of JAMA under Simmons immediately after his graduation from Chicago’s Rush Medical School in 1913. Campion pointed out the following9: Over the years, Fishbein not only established himself as the gifted editor of the most widely read medical journal in the United States; he also learned how to extend his editorial position, how to project his opinions nationwide. He became, as the saying went in those years, a “personality.” TIME referred to him as “the nation’s most ubiquitous, the most widely maligned, and perhaps most influential medico.” In addition to his development of JAMA as an editorial and personal voice, Fishbein also continually railed against “quackery.” Lust, among others, including MacFadden, became Fishbein’s epitome of quackery. When MacFadden became a wealthy man, after his publishing company included popular magazines like True Confessions and True Detective, he began campaigning for the 1936 Republican presidential nomination. In response, a physician submitted, under the initials “K.G.,” a tongue-in-cheek listing of the cabinet that would exist under MacFadden, including the newly created “Secretary of Aviation” for Lust. Lust was a popular figure by this time who conducted such a busy lecture schedule and practice, alternating between the “Yungborns” in Butler, New Jersey, and Tangerine, Florida, that he had become almost as well known as an airline traveler. Lust devoted a complete editorial in Nature’s Path to a response. Although Fishbein had JAMA as a personal editorial outlet, Lust had his own publications. Commencing with the Naturopath and Herald of Health in 1902 (which changed its name to Herald of Health and Naturopath in 1918), Lust continually published this and other monthly journals. In 1919 it became the official journal of the ANA, mailed to all members. Each edition contained the editorial column “Dr. Lust Speaking.” In the early 1920s, the “health fad” movement was reaching its peak in terms of public awareness and interest. As described, somewhat wistfully, in his June 1937 column, Lust announced the approach of the 41st Congress of Natural Healing under his guidance: The progress of our movement could be observed in our wonderful congresses, in 1914 Butler, N.J., 1915 Atlantic City, 1916 in Chicago, 1917 Cleveland, 1918 New York, 1919 Philadelphia, 1920 and 1921 again New York, and 1922 in Washington, D.C., where we had the full support and backing of the Congress of the United States. President Harding received the president and the delegates of our convention and we were the guests of the City of Washington. Through the strenuous efforts of Dr. T.M. Schippel, Hon. Congresswoman Catherine Langley of Kentucky, and eight years of hard work financed and sustained by Dr. Schippel and her powerful friends in Congress, Naturopathy was fully legalized as a healing art in the District of Columbia and the definition was placed on record and the law affirmed and amended by another act which has been fully published over and over again in the official journal of the A.N.A., Naturopath. In 1923 in Chicago, with the help and financing of the great and never-to-be forgotten Dr. Henry Lindlahr, we had a great convention. Not only were all the Naturopaths there but even to an extent our congress was recognized and acknowledged as official and of great importance by the medical people, particularly by the Health Commissioner of Chicago. We held a banquet, and there were discussions covering all platforms of the healing art. It was the first congress in the United States where medicine and Naturopathy in all its branches such as the general old-time Nature Cure, Hydrotherapy and Diet, Osteopathy, Naprapathy, Chiropractic,

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Neuropathy and Physiotherapy were represented on the same platform. The speakers represented every modern school of healing and the movement at that time was in the direction of an entirely recognized and independent school of healing. There were two camps, official medicine and official Naturopathy, the medical camp having all that is good and bad in medicine and surgery and all the other schools of healing that had sold their birthright and trusted to the allurement of organized medicine, such as Homeopaths, Eclectics, Physio-medics, and the Osteopaths to a large extent. The Osteopaths were always in the wrong camp when they went on mixed boards and Dr. Andrew Taylor Still, the father of Osteopathy, told me in 1915 that by compromising with medicine Osteopathy is doomed as the school that could have incorporated all of the natural and biological healing arts. The year following we had the great congress in Los Angeles which has never been duplicated. We had to meet in two hotels because the crowds ran over 10,000. The glorious banquet will never be forgotten and the congress celebrated and demonstrated that the initial and first intent of the A.N.A. to teach the public Natural Living and Nature Cure was realized. We will never forget the glorious week in Los Angeles where the authorities and the whole city joined us. The success of that congress was largely due to the talent of Dr. Fred Hirsch, the successor to Prof. Arnold Ehret and the noble and generous Naturopaths of the A.N.A. of Cal. There was never a second congress like that. Then we had the great congresses of New York in 1925, Indianapolis 1926, Philadelphia 1927, Minneapolis 1928, Portland, Oregon 1929, New York 1930, Milwaukee 1931, Washington, D.C., 1932, Chicago 1933, Denver 1934, San Diego 1935, and Omaha 1936. In 1925 Lust began to try to reach more of the general populace through the lay publication Nature’s Path. The Naturopath and Nature’s Path were later merged because the self-supporting advertising and subscription monies were more available by publication to the general populace than to the members of the association (The Naturopath, 1902–1927; Nature’s Path, 1925–1927; merged 1927–1933; separated 1934–1938; Nature’s Path, 1939–1945). How large a professional movement Lust inspired during this period of naturopathy’s emergence is difficult to gauge. An extensive government survey was not undertaken until 1965. However, as Whorton described in Nature Cures,21 naturopathy had an effect: Those were messages that had enough appeal, evidently, to allow naturopathy to expand steadily through the first decades of the century until by 1923 Lust could estimate that there were nine thousand naturopaths, a “vast army of professional men and women” working on all continents to “rejuvenate and regenerate the world.” His figures were undoubtedly inflated. An independent study [the work of the CCMC discussed later] put the number of naturopaths at “possibly 1500,” allowing that if the “allied groups” that advocated drugless healing under other names [physiotherapy, sanipractic] were added on the total may reach 2500. Yet whatever their numbers, naturopaths had grown into a force not to be ignored. Although Lust’s claim of 9000 naturopaths worldwide is impossible to assess, 5000 practitioners may be a reasonable estimate of the reach of his naturopathy in the United States by the late 1920s and into the 1930s. As Whorton21 reported, the mixer orientation within chiropractic was also becoming a growing presence. This orientation was a philosophy that tended to merge chiropractic and naturopathy in education and practice.22 Although homeopathy has undergone a small revival in recent years, very few MDs now practice it. It is currently mainly of interest to naturopaths, who earn doctor of naturopathy (ND) degrees, and to a few chiropractors. Naturopaths closely resemble

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SECTION 1 

Philosophy of Natural Medicine

chiropractors in that they use spinal manipulative therapy and because so-called mixer chiropractors also use naturopathic methods such as heat, cold, hydrotherapy, physiotherapy, dietary supplements, and even some herbal and homeopathic remedies, which is why the traditional, or “straight,” chiropractors disparagingly call them “medipractors.” Until the middle of the 20th century, a few mixer schools offered both DC and ND degrees, either as alternatives or together after an additional semester of study. Whorton noted a “1930 survey in which some 1,800 chiropractors participated, found, for example, that 1,124 employed hydrotherapy, 1,173 used light therapy, 1,257 provided electrotherapy, and a full 1,352 trusted vibration therapy.”21 In January 1934 Lust commenced republication of the title Naturopath and Herald of Health in addition to Nature’s Path. Each volume opened with his personal column, different for each publication. Both publications were issued through 1938, when the Nature’s Path again became the sole publication until Lust’s death in 1945. After the Universal Directory, Lust continued to write volumes on naturopathic principles, although he was more of a synthesizer, organizer, lecturer, and essayist than a scientific documenter of naturopathic principles. His most enduring contributions may remain his early translations of Kuhne’s and Just’s works. During the 1920s and up until 1937, Lust’s brand of “quackery,” so labeled by Fishbein, was in its most popular phase. Although the institutional markings of the orthodox school had gained ascendancy, before 1937, it had no real therapeutic success in the treatment of disease outside of the broad advancements in public health. Lust’s naturopathy, together with chiropractic and osteopathy, continued to be on the outside looking in, this lack of therapeutic advancement notwithstanding. Practitioners of all three movements were continually prosecuted for practicing medicine without a license, although they often won their cases by establishing to juries that their practices were (even according to the testimony of medical men) not the same as medicine at all. At the time, orthodox practitioners could offer little or no expectation of cure for many diseases, and the “health food and natural health” movement was generally popular. During the 1920s Gaylord Hauser, later to become the health food guru of the Hollywood set, came to Lust as a seriously ill young man. Lust, through the application of the nature cure, removed Hauser’s afflictions and was rewarded by Hauser’s lifelong devotion. His regular columns in Nature’s Path became widely read among the Hollywood set. As noted in Other Healers, Other Cures15: The last big name in Naturopathy was Gaylord Hauser, a Viennese-Born food scientist (as one of his early books identified him) turned to Naturopathy in his later years. He is best remembered for advising the eating of living foods, not dead foods, and for escorting Greta Garbo around. In addition to fresh fruits and vegetables, Hauser’s “Wonder Foods” were skimmed milk, brewer’s yeast, wheat germ, yogurt, and blackstrap molasses. The naturopathic journals of the 1920s and 1930s are instructive. Much of the dietary advice focused on poor eating habits, including the lack of fiber in the diet and an overreliance on red meat as a protein source. More than half a century later in the 1980s, the pronouncements of the orthodox profession, the National Institute of Health, and the National Cancer Institute finally accepted the validity of these early assertions by naturopaths that poor dietary and living habits (particularly smoking) would lead to degenerative diseases, including cancers associated with the lungs, the digestive tract, and the colon. The December 1928 volume of Nature’s Path was the first American publication of the works of Herman J. DeWolff, a Dutch epidemiologist who was one of the first individuals to assert, based on studies of

the incidence of cancer in the Netherlands, that there was a correlation between exposure to petrochemicals and various types of cancers. He saw a connection between chemical fertilizers and their usage in some soils (principally clay) that led to poisons remaining in vegetables after they had arrived at the market and were purchased for consumption. Again, it was 50 years before orthodox medicine began to accept the wisdom of such concerns. As Whorton noted in Nature Cures, naturopaths were less successful than osteopaths and chiropractors in accomplishing professionalization by the elevation of professional standards, including professional education. This occurred despite the formation of a National Board of Naturopathic Examiners of the ANA in 1940. There was constant internal bickering, which “by the 1940s had taken on a more ominous tone.” Although “standards at naturopathic schools were steadily raised from the 1940s on, thanks to both professional idealism and the requirements of state licensing laws,” based on “a perusal of the statutes of the dozen states in which naturopaths were licensed in the late 1940s,” the divisive trends within naturopathy “would not begin to be reversed until the 1970s.” Whorton21 observed that there was no misunderstanding where Lust himself stood on the need for professional standards: Obtaining their own licensing statutes was perceived by alternative practitioners as a critical measure for purging incompetence and quackery from their own rank. “Where there is no official recognition and regulation,” the founder of naturopathy, Benedict Lust maintained, “you will find the plotters, the thieves, the charlatans … [The] riff-raff opportunists bring the whole art into disrepute.” By the time Lust said this, shortly before his death in 1945, frustrating experience had demonstrated that “that is the fate of any science—any profession—which the unjust laws have placed beyond the pale.” In following the evolution of alternative medicine over the first third of the twentieth century, it is essential to keep in mind that constant battle of each system to bring itself within the pale. 

The Emerging Dominance of American Medical Association Medicine In 1937 the status of conventional (allopathic) medicine began to change. The change came with the beginning of the era of “miracle medicine.” Lewis Thomas, in his interesting work The Youngest Science,23 compared his education and internship as a physician with his father’s life as a physician. His father believed that bedside manner was more important than any actual medication offered by the physician. His father went into general surgery so that he could offer some service to his patients that actually made some change in their condition. Thomas pointed out that the major growth of “scientific medicine” until 1937 advanced diagnosis rather than offering any hope of cure. This introduction of “miracle medicine,” the social effects of World War II on health care, and the death of Lust in 1945 all combined to contribute a precipitous decline for naturopathy and natural healing in the United States. (During the war, the necessity for crisis surgical intervention techniques for battlefront conditions encouraged the use of morphine, sulfa drugs, and penicillin for diseases not previously encountered in civilian life by American combat soldiers. This resulted in the rapid development of higher-technology approaches to medicine and highly visible successes.) Lust recognized this, and his editorializing became, if anything, even more strident. From the introduction of sulfa drugs in 1937 to the Salk vaccine’s release in 1955, the American public became used to annual developments of miracle vaccines and antibiotics.

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

Lust died in September 1945 at the Yungborn facility in Butler, New Jersey, preparing to attend the 49th Annual Congress of his American ANA. In August 1945, for the official program of that congress held in October 1945 just after his death, he dictated the following remarks: What is the present condition of Naturopathy? What is its future? I can give my opinion in a very few words. For fifty years I have been in the thick of the fight to bring to the American people the Nature Cure. During that period I have had an opportunity to judge what Naturopathy has done, and can accomplish and the type of men and women, past and present, who make up the Naturopathic ranks. Let us take the present situation first. What is Naturopathy accomplishing? The answer to that is: “Everything.” Naturopathy holds the key for the prevention, alleviation and cure of every ailment, to man and beast alike. It has never failed in the hands of a competent Naturopath. Whatever the body can “catch”—that same body, with proper handling, can eliminate. And that takes in cancer, tumors, arthritis, cataract and the whole gamut of “incurable medical” disease and ailments. During my years of practice I, personally, have seen every type of human ailment and so-called serious “disease” give way to the simple, proven Naturopathic methods. I make no exception to that statement. Now let us see the type of men and women who are the Naturopaths of today. Many of them are fine, upstanding individuals, believing fully in the effectiveness of their chosen profession— willing to give their all for the sake of alleviating human suffering and ready to fight for their rights to the last ditch. More power to them! But there are others who claim to be Naturopaths who are woeful misfits. Yes, and there are outright fakers and cheats masking as Naturopaths. That is the fate of any science—any profession—which the unjust laws have placed beyond the pale. Where there is no official recognition and regulation, you will find the plotters, the thieves, the charlatans operating on the same basis as the conscientious practitioners. And these riff-raff opportunists bring the whole art into disrepute. Frankly such conditions cannot be remedied until suitable safeguards are erected by law, or by the profession itself, around the practice of Naturopathy. That will come in time. Now let us look at the future. What do we see? The gradual recognition of this true healing art—not only because of the efforts of the present conscientious practitioners but because of the bungling, asinine mistakes of orthodox medicine—Naturopathy’s greatest enemy. The fiasco of the sulpha drugs as emphasized disastrously in our armed forces is just one straw in the wind. The murderous Schick test—that deadly “prevention” of diphtheria—is another. All these medical crimes are steadily piling up. They are slowly, but inevitably, creating a public distrust in all things medical. This increasing lack of confidence in the infallibility of Modern Medicine will eventually make itself felt to such an extent that the man on the street will turn upon these self-constituted oppressors and not only demand but force a change. I may not be here to witness this revolution but I believe with all my soul that it is coming. Yes, the future of Naturopathy is indeed bright. It merely requires that each and every true Naturopath carry on—carry on—to the best of his and her abilities. May God bless you all. The effects of postwar events on osteopathy and chiropractic were completely different from the effect on naturopathy. In the early days of osteopathy, there was a significant split between the strict drugless system advocated by A. T. Still (osteopathy’s originator) and the beliefs of many MDs who converted to osteopathy because of its

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therapeutic value. The latter group did not want to abandon all of the techniques they had previously learned and all of the drugs they had previously used when those therapy techniques were sometimes effective. Ultimately, most schools of osteopathy, commencing with the school based in Los Angeles, converted to more of an imitation of modern orthodox medicine. These developments led to more of an accommodation between the California osteopaths and the members of the California Medical Association. (This developing cooperation between the California Osteopathic and Medical Association was one of the major issues leading to the downfall, in 1949, of Fishbein’s editorial voice in JAMA.) Thus osteopathy found a place in professional medicine, at the cost of its drugless healing roots and therapies.9 Naturopathy had become an element of chiropractic education and practice at least as early as 1910 with the founding of the Peerless College of Chiropractic and Naturopathy in Portland, Oregon.22 From this point on, naturopathic education developed in two tracks: schools of naturopathy owned and operated by naturopaths and chiropractic schools that had naturopathic curricula in addition to the core chiropractic programs. These latter schools were a central part of the mixer orientation within chiropractic.22,24 Initial assessments of schools of naturopathy occurred in the 1920s and 1930s. These assessments came from those within, or allied with, allopathy and were therefore hardly unbiased, but much of the information in these assessments seemed credible. The progression of education in naturopathy would be expected to have been similar to that of chiropractic, if somewhat smaller in scale. In this regard, Wardwell noted22: Wiese and Ferguson25 identified 392 different chiropractic schools as having existed in the United States. When those for which there is no evidence of more than a year of operation are eliminated, the number is reduced to 188. Most of them probably produced few graduates—the number of schools increased rapidly to their largest between 1910 and 1926, and then contracted, particularly during the depression of the 1930s and World War II. The history of schools of naturopathy followed much the same pattern. Whorton21 noted in Nature Cures that this was the case. The operators of these schools seemed, at least on the surface, aware of the kind of criticisms to which proprietary trade and professional schools were subjected: limited facilities, limited resources, and an emphasis on collecting revenue versus providing a full professional education.22,24 The leading operators of schools of naturopathy sought, at least on paper, to respond to these criticisms. By letter agreement dated October 7, 1922, four of the most identifiable leaders of naturopathy—Benedict Lust, Joe Shelby Riley, F. W. Collins, and Henry Lindlahr—committed to the formation of the Associated Naturopathic Schools and Colleges of America and committed themselves, as “the Presidents of Naturopathic Schools in the United States of America,” to specific educational minimums “on and after January 2, 1923”: “all matriculants must have a primary school education26 and all naturopath courses must be composed of 4 years of 6 months each.” Additionally, the letter provided that “time allowance or credits may be given to practitioners in the field who desire to take up the naturopathic courses, and to licensed physicians of other methods of healing,” with the amount of such credit being left to each school’s discretion. In the summer and fall of 1927 representatives of the AMA’s Council on Medical Education and Hospitals conducted inspections—unannounced and incognito—of schools of “chiropody, chiropractic, naturopathy, optometry, osteopathy, physical therapy, as well as a large number of institutions.” From these inspections, several reports were generated, including the Council’s report on “Schools of Chiropractic and Naturopathy in the United States,”

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SECTION 1 

Philosophy of Natural Medicine

which appeared first as part of the Council’s Annual Report, 1928, and later as reprinted in JAMA. The report identified 40 schools of chiropractic and 10 schools of naturopathy and detailed the inspections of “some schools of Chiropractic and of Naturopathy”: Palmer School of Chiropractic (a straight school); National College of Chiropractic (a mixer school that was reported as having recently purchased and assimilated Lindlahr College of Natural Therapeutics); Los Angeles College of Chiropractic (another leading mixer school); the combined American School of Naturopathy, Inc. and American School of Chiropractic, Inc. (Lust’s own New York City schools, although Lust was observed to have been “in Florida” at the time of the inspections); and the Naturopathic College and Hospital of Philadelphia. The reports were predictably negative with regard to facilities, resources, and the clearly proprietary nature of the establishments. Louis Reed of the Committee on the Costs of Medical Care (CCMC), in discussing “naturopathic schools,”24 relied heavily on this report from the AMA’s Council and observed that “in 1927, according to the American Medical Association, there existed twelve naturopathic colleges with not over 200 students. These figures would probably hold good for the present time.” Reed also concluded that there were “a considerable number of miscellaneous drugless healers of a type similar to chiropractors practice in this country” as of 1932 and that “the naturopaths form the largest group of these practitioners.… Of these various cults, only the naturopaths and the sanipractors have any considerable membership. Many of the (other) cults are really part of the naturopathic group.”24 As to numbers of drugless practitioners, Reed observed that “only the roughest estimate can be made—probably there are about 2500,” of which naturopaths “number possibly 1500,” and sanipractors—“only the name distinguishes sanipractors from the naturopaths”—numbered some 500 in their Washington state “stronghold.” Reed also observed that as of 1932: “A few states—Connecticut, Florida, Oregon, South Carolina, Utah, Washington and the District of Columbia—provide for licensing of naturopaths as limited practitioners.… In addition to those mentioned, certain states (Alabama, Colorado, Illinois, Indiana, Michigan, Ohio, Pennsylvania, New Jersey, and Wyoming) make (other) provision for the licensing of drugless or limited practitioners.”24 Reed’s work for the CCMC, although clearly biased against all of the healing philosophies he identified as “medical cults” (a la Fishbein), principally osteopathy, chiropractic, and naturopathy, was the only work that attempted to survey the presence and effect of these schools of healing in the United States in the 1920s and 1930s.27 A decade later, in April 1945, another work of this kind appeared in the Rhode Island Medical Journal. The article, “Naturopathic Legislation and Education,” was written by the Rhode Island Medical Society’s executive secretary, John E. Farrell, to set out some of the society’s reasons for opposing legislation that would license naturopathy in Rhode Island. The article noted that according to the 1942–1943 Report of the Committee on Education of the ANA, 13 schools of naturopathy in the United States met the criteria of the ANA; the article went on to make a lengthy “Report on Schools” through visits to most of the identified schools.28 The predictable criticisms of these schools as underfinanced, underresourced, and proprietary in nature appeared once again, although by actual detail of description, National College (Chicago) and Western States (Portland) seemed to be well-established, functioning mixer schools of chiropractic and naturopathy. The effect on chiropractic of the post–World War II years was somewhat different. Because of educational recognition under the G.I. Bill, the number of chiropractors in the country grew

substantially, and their effect on the populace grew accordingly. The sect eventually grew powerful enough in terms of numbers and economic clout that it could pose a legal challenge to the orthodox monopoly of the AMA. However, in the immediate postwar years, the AMA gained tremendous political clout. Combined with the American Legion and the National Board of Realtors,29 these three groups posed a powerful political triumvirate before the U.S. Congress. These years, called the years of the “great fear” in Caute’s book by that name,30 were the years during which to be unorthodox was to be “un-American.” Across the country, courts began to take the view that naturopaths were not truly doctors because they espoused doctrines from “the dark ages of medicine” (something American medicine had apparently come out of in 1937) and that drugless healers were intended by law to operate without “drugs” (which became defined as anything a person would ingest or apply externally for any remedial medical purpose). In this regard, the Washington State Supreme Court case of Kelly v. Carroll31 and the Arizona State Supreme Court case of Kuts-Cheraux v. Wilson document how significant limitations were placed on naturopaths under the guise of calling them “drugless healers.” In the state of Tennessee, as a reaction to the 1939 publication of the book Back to Eden by herbalist Jethro Kloss, court action initiated by the Tennessee State Medical Association led first to the publishers being forbidden to advertise the book for any therapeutic purpose. They were allowed only to acknowledge that it was in stock. Then, after a serious licensing scandal during the war years, the Tennessee State Legislature declared the practice of naturopathy in the state of Tennessee to be a gross misdemeanor, punishable by up to 1 year in jail. Although it was under considerable public pressure in those years, the ANA undertook some of its most scholarly work, coordinating all the systems of naturopathy under commission. This resulted in the publication of a basic textbook on naturopathy (Basic Naturopathy, published in 1948 by the ANA32) and a significant work compiling all the known theories of botanical medicine (as commissioned by the ANA’s successor after its 1950 name change to the American Naturopathic Physicians and Surgeons Association), the Naturae Medicina, published in 1953.33 Naturopathic medicine began splintering when Lust’s ANA was succeeded by six different organizations in the mid-1950s. The primary organizations among these were the successor to the ANA, which underwent a name change in 1950 to the American Naturopathic Physician and Surgeon’s Association and subsequently changed to the American Association of Naturopathic Physicians (AANP) in 1956, and the International Society of Naturopathic Physicians formed under the leadership of M. T. Campenella of Florida shortly after Lust’s death, with its American offshoot, the National Association of Naturopathic Physicians. In the face of the AMA’s determination to eliminate chiropractic, and with it, naturopathy—healing philosophies that were linked through the mixer orientation within chiropractic (during the 1930s and through the 1960s the majority camp within a divided chiropractic)—naturopathy went through a period of decline described by Hans Baer (see Bibliography). Walter Wardwell was a sociology professor who became an early leader in what developed as a subspecialty in the 1950s: medical sociology. His earliest work, starting with his doctoral dissertation (1951) at Harvard, focused on chiropractic as an example of a marginalized health profession (see Bibliography). As early as his doctoral dissertation, Wardwell discussed naturopathy as an adjunct discipline to

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

chiropractic in the context of the continuing division of chiropractic into mixers and straights. As he later noted34: Comparison of the survival of chiropractic with that of osteopathy and naturopathy is a quite different matter which does not involve metaphysical or epistemological differences between them. Furthermore, the overlap in theory between chiropractic, osteopathy and naturopathy is very great. Differences between osteopathic and chiropractic manipulative treatment appear to be more a matter of who applies the technique rather than differences in technique itself. The distinction between chiropractors and naturopaths is even more blurred because they often trained at the same schools and sometimes they studied both fields simultaneously. As recently as 1948, three of the currently accredited chiropractic colleges offered N.D. (Doctor of Naturopathy) and D.C. (Doctor of Chiropractic) degrees. In this context he described naturopathy as a school of healing that became extinct as two historical factors converged: the death of Lust in 1945, leaving naturopathy without its “founder,” and the mandate in the early 1950s by the major mixers’ professional group, the National Chiropractic Association (NCA), that it would no longer accredit chiropractic schools that granted degrees in naturopathy: In the case of naturopathy, chiropractic’s victory is nearly complete. Although there may still be up to 2000 naturopaths in practice35 with naturopaths licensed in a few states, and one small school in Portland, Oregon, still offers naturopathic degrees, none of the schools that formerly offered both chiropractic and naturopathic degrees currently does so. With practically no new recruits entering the profession, naturopathy must disappear. By the late 1970s, Wardwell had learned of efforts in the Pacific Northwest to keep naturopathy alive. In his chapter in the Handbook of Medical Sociology, Wardwell noted this presence in the Northwest (which had received no mention in the first two editions in 1963 and 1972)36: The accrediting of chiropractic colleges is encouraging uniformity, not only in curricula but in scope of practice. Those colleges that formerly offered the Doctor of Naturopathy (N.D.) as well as the D.C. degree have ceased doing so, leaving naturopathy with only one remaining small college in Portland, Oregon. In his masterwork, Chiropractic: History and Evolution of a New Profession (1992),22 Wardwell devoted substantial attention to the effect of naturopathy on the mixer orientation within chiropractic and traced naturopathy’s final educational decline to the untimely death in 1954 of William A. Budden, DC, ND, the president of the Western States Chiropractic College (WSCC; Portland, Oregon). After Budden’s death, the WSCC continued to teach naturopathy until 1958 but dropped its ND degree program in 1956. This was the last resistance to the position of the accrediting committee of the NCA, and no chiropractic ND programs remained. Wardwell observed, though, that the seeds of a naturopathic reemergence had been planted in the Northwest after Budden’s death and that naturopathy might survive. The last ND diplomas were granted at the WSCC in 1958 to students who were enrolled in the ND program at the time of Budden’s death. Brinker37 noted the following: Political pressure from the chiropractic profession had begun in the late 1940s to force chiropractic schools to relinquish programs granting naturopathic degrees. After threatening loss of accreditation, the National Chiropractic Association finally forced Western States College to drop its School of Naturopathy in 1956, and it became exclusively Western States Chiropractic College.

43

Efforts to keep naturopathy alive through education and licensure were examined by two reports prepared in 1958, a time when the Utah legislature was reexamining naturopathy’s licensure in the aftermath of a case from the Utah Supreme Court that had dealt its practicing NDs a crippling blow. The first was A Study of the Healing Arts With a Particular Emphasis Upon Naturopathy (November 1958), prepared as “A Report to the Utah Legislative Council” by legislative council staff. As part of its work, the staff conducted inquiries of and site visits to seven schools accredited by the Utah Naturopathy Examining Board as of August 1957. Separately, the Bureau of Economic and Business Research38 of the University of Utah (BEBR) undertook a study focusing on schools that had granted naturopathy degrees and produced Survey of Naturopathic Schools (“Prepared for the Utah State Medical Society,” December 1958). Preparation of the study was, as noted in the title, undertaken by the university research program at the request of the state medical society, but the preparation of the study was independent, and “no attempt was made by that group to influence the results of the study” (Foreword and Acknowledgements). The BEBR study, done with the requested cooperation of investigators from five other universities located in various sections of the United States, surveyed all of the schools listed by Utah licensees as schools of graduation or schools attended, using records maintained by the Utah Department of Business Registration.10 Because the state of naturopathic education in the 1950s is relevant, some observations from this study are worth noting39: One of the most important results to emerge from this study is that there are virtually no schools now teaching naturopathy. Of the 26 schools investigated during this study, only 9 were still in existence in the fall of 1958. Of these nine, only three are now granting naturopathic degrees, and two others are teaching naturopathy. Of the three schools granting ND degrees, the study found that one school, Sierra States University in California, began offering a “postgraduate” ND degree after the most highly respected chiropractic program in the country, Los Angeles College of Chiropractic, had discontinued its ND degree program in 1948. National College of Naturopathic Medicine (NCNM), the Oregon school, had—in 1957, its first year of operation—four ND students who were starting at NCNM and 60 enrolled “postgraduate” DCs pursuing ND degrees. The school had been recognized by the Utah examining board but had not yet granted degrees. The third school granting ND degrees as of 1957 to 1958 was the Central States College of Physiatrics in Eaton, Ohio, essentially the one-man operation of H. Riley Spitler, author of Basic Naturopathy (published by the ANA in 1948). This school granted a doctor of mechanotherapy (DM) degree, recognized in only Ohio and Alabama by law, or an ND degree to anyone who sought licensure in a state where an ND degree would qualify a graduate for licensure. The course of study for both degrees was the same, and the school had graduated 10 students in the previous 2 years. Its ND degrees were recognized in Utah. By 1955, the AANP, as it ultimately became known, had recognized only two schools of naturopathic medicine, the Central States College of Physiatrics in Eaton, Ohio, under the leadership of H. Riley Spitler, and Western States College of Chiropractic and Naturopathy located outside Portland, Oregon, under the leadership of W. A. Budden. Budden was a Lindlahr graduate and among the group that took over control of the Lindlahr College after Lindlahr’s death in the 1920s. He moved west in 1929 when the northwestern states, including Oregon, became a bastion for naturopaths in this country.

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This state of affairs was accurately described by Homola40 in his book on the history and evolution of chiropractic: As of 1958, only five states (Arizona, Connecticut, Oregon, Virginia and Utah) separately classified and provided licensing provisions for the naturopath. A few states, however, did permit licensing of drugless healers following examination by [a] board. (A good number of states have repealed their laws licensing naturopaths in recent years.) Chiropractic schools that employ the use of physiotherapy teach a course that is very similar to the practice of naturopathy. Likewise, the three or four naturopathic schools still operating today have a curriculum similar to that of many chiropractic colleges. In fact, at least four chiropractic colleges awarded naturopathic degrees along with the chiropractic degree before they came under the jurisdiction of the national Chiropractic Association. With the approval of this organization, the schools were prohibited from issuing naturopathic degrees. This practically amounted to a death-dealing blow to the profession of naturopathy.40 In 1967 the U.S. Department of Health, Education, and Welfare; the Public Health Service; and the National Center for Health Statistics (NCHS) published Public Health Service Publication No. 1758, State Licensing of Health Occupations. With the assistance of the Council of State Governments, the NCHS collected data regarding the licensure of health professionals at the state level. “Chapter 8: Naturopaths” recorded the available data for the naturopathic profession as of the mid-1960s. In summary, the NCHS identified five states and the District of Columbia as licensing naturopaths as of 1967: Arizona, Connecticut, Hawaii, Oregon, and Utah. California and Florida were identified as renewing existing licenses but granting no new licenses. The publication reported that by 1965, California had renewed 66 licenses and Florida, 136. Licenses in effect by state were as follows: Arizona (100), Connecticut (47), Hawaii (14), Oregon (148), and Utah (42). No numbers were provided for the District of Columbia. The report stated the following41: In addition to Doctors of Naturopathy (ND) there are other limited branches of medicine; these have not been included in the study. In the State of Washington the Drugless Therapeutics Examining Committee functions (for such licensure). The Ohio law states which branches are to be specified on certificates issued by the State Medical Board to limited practitioners. No attempt has been made to collect information on these drugless healers who are few in number. Active state practitioners were also numbered (although the reason for the differentiation is not clear), as follows: Arizona (53), Connecticut (29), Hawaii (13), and Oregon (121). Given the existence of approximately 50 practitioners at the time in Washington, and some practicing in Idaho under a decision of the Idaho Supreme Court, there appear to have been perhaps as many as 600 to 700 remaining naturopaths practicing at the end of the 1960s.42 According to documentation provided to the federal Department of Health, Education, and Welfare in 1968 by the again-remaining professional association—the National Association of Naturopathic Physicians—only 17 degrees were granted from 1960 to 1968. By 1968, this association had 168 members and estimated that there were perhaps 500 “active” naturopaths in the United States. Congress adopted Medicare in 1965. The legislation covered payment for the services of physicians (essentially MDs and DOs), hospital services, and “other therapeutic services” that would commonly be provided

through these conventional means. As Wardwell reported,22 in 1967, Congress directed the secretary of the Department of Health, Education, and Welfare (HEW), Wilbur Cohen, to study the inclusion services of “additional types of licensed practitioners.” The surgeon general and other HEW staff prepared the resulting Independent Practitioners Under Medicare using advisory committees only (Wardwell served on the Expert Review Committee for Chiropractic and Naturopathy), which actually had little input. This report documented the ebb tide of naturopathy’s “period of decline,” as Baer later labeled it.43 The section of the report Naturopathy concluded that as of 1968: Naturopathic theory and practice are not based on the body of basic knowledge related to health, disease, and health care which has been widely accepted by the scientific community. Moreover, irrespective of its theory, the scope and quality of naturopathic education do not prepare the practitioner to make an adequate diagnosis and provide adequate treatment. Considering the state of the profession in 1968, these negative assessments were hardly unexpected. 

THE MODERN REJUVENATION After the counterculture years of the late 1960s and feeding of an American disenchantment with organized medicine that began after the miracle-drug era faded, exposing some of orthodox medicine’s limitations, alternative medicine began to gain new respect. Naturopathic medicine underwent an era of rejuvenation as a late-1970s consumer interest in more “holistic” medicine began to emerge. As succinctly described in Cassedy’s44 Medicine in America: A Short History, this phenomenon, which was not limited to naturopathic medicine, was consistent with the modern and continuing “search for health beyond orthodox medicine”: It should not have been surprising to anyone that certain organized therapeutic sects continue to exist in mid–twentieth century America as successful and conspicuous alternatives to regular medicine. This is not to say that they offer the same threats to the medical establishment or play the same roles as their nineteenth-century counterparts had, as complete therapeutic systems. But they do continue to hold a strong collective appeal for individuals who mistrust or are somehow disenchanted with mainline medicine. They have appealed also to antiauthoritarian sentiments that flourish throughout society. Moreover, as earlier, they satisfy various needs that regular medicine continues to neglect or ignore. The same author, in describing the post–World War II decades and the changing fortunes of such healing theories as naturopathic medicine, observed as follows: The period also brought about the renewal or updating of certain previously widely used therapies and considerable experimentation with others, some of them exotic. To an extent this trend represented the rediscovery by trained physicians, nurses, and other regular health professionals of certain values and older styles of therapy. The participation of such professionals proved to be an essential ingredient in the rebirth of several such therapies. However, the major reason for the new successes was the wide-spread active interest and involvement of America’s literate lay people in the search for more personal or humane forms of treatment. As another author, John Duffy,45 observed in From Humors to Medical Science:

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

Since health is too closely related to cultural, social, and economic factors to be left exclusively to doctors, American lay people have always engaged in do-it-yourself medicine, resorted to “irregulars and quacks,” and supported health movements. As a result of the current fad for physical fitness, our streets are beset by sweat-suited individuals of all ages doggedly jogging their way to health and long life. In addition, stores selling “natural” foods are flourishing, physical fitness salons have become a major business, and anti-smoking and weight-loss clinics and workshops are attracting thousands of individuals bent on leading cleaner and leaner lives. And those for whom physical activity in itself is not enough are seeking physical and mental well-being through faith healing, yoga, and a host of major and minor gurus. When neither mental effort nor physical exercise can solve medical problems, the sceptics of modern medicine can always turn to the irregulars. A recent estimate places a number of Americans who have relied on an irregular practitioner at some time in their lives at 60 million, and, aided by the high cost of orthodox medicine, irregular medical practice appears to be on the rise. At the beginning of this period of rejuvenation, the profession’s educational institutions had dwindled to one, the National College of Naturopathic Medicine (which had branches in Seattle, Washington, and Portland, Oregon), which was founded after the death of R. A. Budden and the conversion of Western States College to a straight school of chiropractic. Kruger’s15 book Other Healers, Other Cures described it as follows in 1974: Today, Naturopaths in seventeen states are licensed to diagnose, treat, and prescribe for any human disease through the use of air, light, heat, herbs, nutrition, electrotherapy, physiotherapy, manipulations, and minor surgery. At present, one can earn an D.N. [a misnomer, actually—N.D.] degree at the National College of Naturopathic Medicine in Seattle and Emporia, Kansas, [where, by contract, the first 2 years of the 4-year medical education were then taught], or the new North American Naturopathic Institute in North Arlington, New Jersey [there is also a school in Montreal]. The four-year curriculum covers many standard medical courses—anatomy, bacteriology, urology, pathology, physiology, X-ray reading etc.—but also includes botanical medicine, hydrotherapy, electrotherapy, and manipulative technique. The public, by the late 1970s, was particularly ripe for another rejuvenation of naturopathy’s brand of “alternative” health care. As described in Murphy’s Enter the Physician: The Transformation of Domestic Medicine, 1760–1860, when discussing this cyclical rejuvenation in the mid-20th century46: Contemporary crusaders still stress prevention as the layperson’s primary duty, but a growing chorus is calling for every person to assume the newly proactive role in his or her own health care. What would this entail? There are probably as many answers to this question as there are respondents, but it is striking to note how many of the solutions would have been familiar to our ancestors who lived between 1760 and 1860. One recurring idea, for instance, is that each person knows his or her own constitution history the best and therefore has a duty to communicate that knowledge to medical personnel. Another is a refurbished concept of vis medicatrix naturae, the belief that many diseases are self-limiting and therefore do not require much medical intervention—and certainly not the amount or the sort to which contemporary Americans are accustomed. Most significantly, today’s analysts are calling

45

on professionals and nonprofessionals to build and nurture a healthcare partnership very much like that envisioned by 19th-century health publicists: a partnership based on mutual respect, clear understanding, and faithful execution. In that scenario, both as it originally evolved and in its updated version, it is the doctor who directs treatment, but crucial to a successful outcome are the informed and responsible actions of the patients, other caregivers, and the patient’s family and friends. In 1978 the John Bastyr College of Naturopathic Medicine was formed in Seattle, Washington, by Joseph E. Pizzorno, ND (founding president), Lester E. Griffith, ND, and William Mitchell, ND (all graduates of the National College of Naturopathic Medicine), and Sheila Quinn, who felt that it was necessary to have more institutions devoted to naturopathic care and the teaching of naturopathic therapeutics. To differentiate Bastyr from the other “irregular”45 schools, Pizzorno coined the term science-based natural medicine and developed the curriculum to implement it. Bastyr’s cofounder and first president, Joseph Pizzorno, recognized that “anecdotal and unverified ‘cures’, particularly when associated with unusual therapies do our cause little good.” Consequently, instruction at the school “concentrated more on the scientifically verifiable aspects of natural medicine and less on the relatively anecdotal nature cure aspects.”21 In Other Healers, Unorthodox Medicine in America,47 a volume written to provide “a scholarly perspective on unorthodox movements and practices that have arisen in the United States” (from the editor’s preface), author Martin Kauffman, a modern expert in homeopathy from the Department of History at Westfield State College, detailed Bastyr’s homeopathic requirements to graduate: In 1978, three naturopathic practitioners in Seattle founded the John Bastyr College of Naturopathic Medicine. During the sixth quarter all students at that school are required to take 44 hours of course work in homeopathy, after which they may elect another 66 hours and up to 238 hours of clinical homeopathic instruction. The significance of the naturopathic schools to the resurgence of homeopathy is demonstrated by the fact that “about one third of the graduating class specialized in homeopathic practice, a total of about 50 each year in all.”47 During the late 1970s, other naturopathic doctors also recognized the need to establish educational institutions for students of naturopathic medicine; subsequent efforts included colleges in Arizona (the Arizona College of Naturopathic Medicine), Oregon (the American College of Naturopathic Medicine), and California (the Pacific College of Naturopathic Medicine). Unfortunately, none of these three survived. As public demand for natural healing grew in the 1980s and 1990s, the emerging profession continued to grow a breadth and quality of educational opportunity for those seeking accredited doctorate-level programs in naturopathic medicine. With thriving enrollments at Bastyr and National College, the Council on Naturopathic Medicine was founded in 1978 to establish and oversee educational standards, and today it is recognized by the U.S. Secretary of Education as the national accrediting agency for programs leading to the doctor of naturopathic medicine (ND or NMD) or doctor of naturopathy (ND) degree. To further build on the cornerstone of accredited education and ensure educational quality, in 1986 the Naturopathic Physician Licensing Examination became the first national board examination for graduates; today, graduates must pass a two-part medical examination in biomedical and clinical sciences before they are eligible to use the title “ND.” This examination is modeled after the conventional medical board examination for allopathic graduates, the U.S. Medical Licensing Exam, which assigns the “MD” license. This training was described in detail in a report

46

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from 2001 by the University of California San Francisco Center for Health Professions: “Naturopathic physicians are typically trained in a wide array of alternative therapies including herbology, homeopathy, massage, hydrotherapy, physical medicine, behavioral medicine, Traditional Chinese medicine, Ayurvedic medicine, acupuncture, and nutrition therapy, as well as clinical practices such as minor surgery, pharmacology and obstetrics.”48 With educational standards set, throughout the 1990s and 2000s, a select group of new programs and institutions attained accreditation status with the Council on Naturopathic Medicine: Southwest College of Naturopathic Medicine and Health Sciences, Tempe, Arizona; the College of Naturopathic Medicine at the University of Bridgeport, Connecticut; the Canadian College of Naturopathic Medicine, Toronto, Ontario; and, in 2011, the Boucher Institute of Naturopathic Medicine, British Columbia, Canada. The establishment of multiple geographic locations for this type of education paves a solid future for the profession, providing hundreds of newly graduated naturopathic doctors every year in the United States and Canada. There are favorable commentaries on the current state of naturopathic medicine. Other Healers, Unorthodox Medicine in America47 is a volume written to provide “a scholarly perspective on unorthodox movements and practices that have arisen in the United States.” As described in the Encyclopedia of Alternative Health Care by Olsen49: While naturopathic medicine is now legal (in several states), many naturopaths practicing in other states are old-timers, practicing under their original “drugless therapy” licenses, issued before laws prohibiting new naturopathic practices went into effect. In cooperation with regional associations, the AANP has won licensure and scope-of-practice protection at a steady rate on par with the growth of schools accredited by the Association of Accredited Naturopathic Medical Colleges. As of 2011, 15 U.S. states, the District of Columbia, five Canadian provinces, and the U.S. territories of Puerto Rico and the U.S. Virgin Islands regulate the naturopathic profession (Box 3.1). Baer’s interest in the evolution of chiropractic as a philosophy of healing led him to Wardwell’s work and to Wardwell’s earlier scholarship, which had been tied to the mixer orientation within chiropractic. Baer took note of his descriptions of naturopathy as a near-extinct philosophy. Predictions of extinction were consistent among the assessments of social scientists in the 1970s and continued into the mid-1980s. Twaddle and Hessler, Rosengren, Whorton, and most notably, Wardwell all discussed naturopathy as a once-observable but marginalized philosophy of health and healing at odds with the conventional medical claims of a scientific medicine (see Bibliography). These social scientists placed naturopathy’s demise sometime in the 1950s when chiropractic severed its open naturopathic link by terminating ND programs. Baer, before Wardwell, took special note of Bastyr and the professionalization represented by its scientific medicine–based curriculum and the publication of a John Bastyr College of Naturopathic Medicine project, The Textbook of Natural Medicine. In his 1992 Medical Anthropology article43 “The Potential Rejuvena­ tion of American Naturopathy as a Consequence of the Holistic Health Movement,” Baer detailed his own view of Naturopathy’s “three stages of development” noted at the outset of this chapter. Besides relying on material covered in the original chapter of “The History of Naturopathic Medicine,” which first appeared in 1985, Baer covered much of the new material regarding the emerging (1900–1930s) and declining (1940– 1970s) stages of naturopathy. Baer particularly broke new ground with his recognition of a “potential rejuvenation” of naturopathy as naturopathic medicine and

BOX 3.1  States/Districts/Provinces That

Regulate the Naturopathic Profession (updated 2018) States Alaska Arizona California Colorado Connecticut Hawaii Idaho Kansas Maine Massachusetts Minnesota Montana New Hampshire North Dakota Oregon Pennsylvania

Rhode Island Utah Vermont Washington  Districts and Territories District of Columbia Puerto Rico U.S. Virgin Islands  Provinces Alberta British Columbia Manitoba Nova Scotia Ontario Saskatchewan

his recognition that the profession had knowingly or unknowingly adopted a recognized survival strategy as a matter of organizational policy: professionalization. Baer also advanced a theory regarding the “potential rejuvenation” as tied to the emergence in the 1970s of holistic medicine. Holistic medicine, as a philosophy of healing, had a cultural affinity with the eclecticism inherent in naturopathic philosophy. In his 2001 book50 Biomedicine and Alternative Healing Systems in America, Baer updated this view of the status of naturopathic medicine in a chapter entitled “Naturopathy and Acupuncture as Secondary Professionalized Heterodox Medical Systems.” With the passage of the additional 10 years, Baer observed50: Unlike chiropractic, which no longer poses a serious threat to biomedicine because of its status as a specialty emphasizing spinal manipulation, a rejuvenated naturopathy finds itself in direct competition with biomedicine because both systems claim to provide a comprehensive approach to health care. As osteopathy and chiropractic did earlier, naturopathy … [is] increasingly incorporating the theory and social organization of biomedicine. [N]aturopathy with [its] reductionist philosophy and [its] focus on individual responsibility for healthy living may well undergo further growth in an era of growing health costs. 

THE 21ST CENTURY AWAITS Baer carried his examination of the sociopolitical aspects forward in his 2001 article “The Sociopolitical Status of U.S. Naturopathy at the Dawn of the 21st Century,”51 which examined the state of naturopathic medicine as it prepared to enter the 21st century. Although “professionalized naturopathy has undergone tremendous growth and legitimization since the late 1970s, nevertheless, it finds itself in a tenuous situation at the dawn of the twenty-first century in that its strength is confined primarily to the Far West and New England; it faces increasing competition from the partially professionalized and lay naturopaths; and it faces the danger of being overshadowed by a powerful biomedical system that is increasingly incorporating aspects of holistic health into its own practice.”

CHAPTER 3 

The History of Naturopathic Medicine: Origins and Overview

He offered no definitive answers to these questions of naturopathic medicine’s future, but he also highlighted areas needing further attention by social scientists: continued exploration of the reasons for naturopathy’s decline and rejuvenation and continued study of the naturopathic profession in recognition of its state of professionalization. In closing, Baer observed: “In sum, while changes in the popular ideas about health and healing unleashed the social forces that enabled professional naturopathy to get back on its feet, those same social forces may overwhelm its core claim to being a unique, natural approach to healing.” Whorton expressed the view that in many respects the transition from the marginalized naturopathy to the professionalized naturopathic medicine has now been accomplished.52 He traced his view of this transformation as part of the larger transformation “from alternative medicine to complementary medicine” on the part of osteopathy, chiropractic, and naturopathy. Whorton described the factors that allowed this transformation even after the death of Lust in 1945: the issue of the “field’s lack of a scientific basis” was determined internally when the “died-in-the-wool believers in ‘nature cure’” were outlasted by the “liberal practitioners belonging to the so-called western group, naturopaths concentrated in the western states who recognized the validity of mainstream medicine’s scientific foundation and sought to incorporate biomedical science into their own system and apply it under the guidelines of naturopathic philosophy.” As Whorton noted, “a key figure among the pseudomedicals was John Bastyr—a practitioner in Seattle since the 1930s, and particularly wellknown for his advocacy of natural childbirth.” Bastyr, Whorton noted, “recognized the necessity of naturopathy staying abreast of advances in

47

biomedical science and applying those advances ‘in ways consistent with naturopathic principles.’”21 Bastyr was directly involved with the formation and maintenance of the NCNM during the years of naturopathy’s decline and lived to see much of “the short history of John Bastyr College [of Naturopathic Medicine] ... the most compelling illustration of the triumphant rebirth of naturopathy as naturopathic medicine.”21 Bastyr has been called the “father of modern naturopathic medicine” by Pizzorno, ND,52 the moving spirit behind the professionalization of naturopathic medicine and the founding president of Bastyr University. No individual has carried the practice of NDs in the United States in the way that Lust did, but Bastyr and the others profiled by Kirchfeld and Boyle in Nature Doctors kept naturopathy alive during its decline in the 1950s and 1960s so that it could, in time, reemerge. The movement continues to grow, and thus the effect of natural healing has come full circle. In an era where the statistical number of persons born who are expected to contract cancer, now recognized as a degenerative disease, has increased rather than declined and where the incidence of other degenerative diseases (arthritis, arteriosclerosis, atherosclerosis, etc.) has increased in direct relation to the lengthening of life expectancies produced by improved sanitation and nutrition (although speciously claimed by AMA medicine to be the result of their therapies), the early teachings of Lust, Lindlahr, and others appear to have more validity than ever.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Starr P. Social Transformation of American Medicine. New York: Basic Books; 1983. 2. Griggs B. Green Pharmacy. London: Jill: Norman, & Hobhouse; 1981. 3. Medical Protestants Haller J. The Eclectics in American Medicine. Carbondale, IL: Southern Illinois University Press; 1994. 4. Whorton J. Crusaders for Fitness. Princeton, NJ: Princeton Press; 1982. 5. Rothstein W. American Physicians in the 19th Century. Baltimore: Johns Hopkins Press; 1972. 6. Haller J. American Medicine in Transition, 1850–1910. Urbana, IL: University of Illinois Press; 1981. 7. Rosen G. The Structure of American Medical Practice. Philadelphia: University of Pennsylvania; 1983. 8. Brown ER. Rockefeller Medicine Men. Berkeley, CA: University of California Press; 1978. 9. Campion F. AMA & US Health Policy Since 1940. Chicago: AMA Publishers; 1984. 10. Burrows J. Organized Medicine in the Progressive Era. Baltimore: Johns Hopkins Press; 1977. 11. Coulter H. Divided Legacy. Vol. 2. Washington, DC: Wehawken Books; 1973. 12. Salmon JW. Alternative Medicines. New York: Tavistock; 1984. 13. Gevitz N. The D.O.’s. Baltimore: Johns Hopkins Press; 1982. 14. Silberger J. Mary Baker Eddy. Boston: Little Brown; 1980. 15. Lindlahr H. Philosophy of Natural Therapeutics. Vol. 1. England: Maidstone: Maidstone Osteopathic; 1918. 16. Lust B. Universal Directory of Naturopathy. Butler, NJ: Lust; 1918. 17. Kruger H. Other Healers, Other Cures. A Guide to Alternative Medicine. New York: Bobbs-Merrill; 1974. 18. Kellogg JH. New Dietetics. Battle Creek, MI: Modern Medical Publications; 1923. 19. Ernst R. Weakness Is a Crime: The Life of Bernarr MacFadden. Syracuse, NY: Syracuse University Press; 1991. 20. Whorton J. Inner Hygiene: Constipation & the Pursuit of Health in Modern Society. New York: Oxford University Press; 2000. 21. Whorton J. Nature Cures: The History of Alternative Medicine in America. New York: Oxford University Press; 2002. 22. Wardwell WI. Chiropractic; History and Evolution of a New Practice. St. Louis: Mosby; 1992. 23. Thomas L. The Youngest Science. Boston: Viking; 1983. 24. Reed L. The Healing Cults. Publication No. 16 of the Committee on the Costs of Medical Care. Chicago: University Press; 1932. 25. Wiese G, Ferguson A. How many chiropractic schools? An analysis of institutions that offered the D.C. degree. Chiropract Hist. 1988;8(1): 27–36. 26. “Primary education”—circa 1922—was an eighth-grade education, and this educational base would have been the same as that required by chiropractic. 27. The results of Reed’s work are also summarized in the CCMC’s Publication No. 27, “The Costs of Medical Care” (Falk, Rorem, and Ring [1933], p. 292), as “Naturopaths and Other Drugless Healers.” 28. With lengthy discussion of Central States College of Physiatrics (Eaton, Ohio), the Colorado Mineral Health School (Denver), Columbia College of Naturopathy (Kansas City), First National University of Naturopathy (Newark, New Jersey, earlier the United States School), the Metropolitan College (Cleveland), the Nashville College of Drugless Therapy (Tennessee), the National College of Drugless Physicians (part of the National College of Chiropractic, Chicago), the Polytechnic College and Clinic of Natural Therapeutics (Fort Wayne, Indiana), the Southern University of Naturopathy and Physio-Medicine (Miami), the University of Natural Healing Arts (Denver), and the Western States College (Portland, Oregon). 29. Goulden J. The Best Years. New York: Atheneum; 1976. 30. Caute D. The Great Fear. New York: Simon & Schuster; 1978. 31. The defendant was Otis G. Carroll of Spokane, Washington. He and his brother, Robert V. Carroll, Sr., of Seattle, were longtime associates of Benedict Lust. As members of Lust’s American Naturopathic Association, they had advanced naturopathy’s presence in Washington State through the Washington State Naturopathic Association.

32. Spitler HR. Basic Naturopathy. Des Moines: ANA; 1948. 33. Kuts-Cheraux AW. Naturae Medicina. Des Moines: ANPSA; 1953. 34. Wardwell WI. Comparative factors in the survival of chiropractic: a comparative view. Sociol Symp. 1978;22:6–17. 35. As to those calling themselves naturopaths, this number was considerably too high, as will become apparent. 36. Wardwell WI. Limited and marginal practitioners. In: Freeman H, Levine S, Reeder LG, eds. Handbook of Medical Sociology. Upper Saddle River, NJ: Prentice-Hall; 1979:240–242. 37. Brinker F. The role of botanical medicine in 100 years of American naturopathy. Herbal Gram. 1998;42:49–59. 38. Now the National Bureau of Economic Research. 39. Bureau of Economic and Business Research. Survey of Naturopathic Schools. Salt Lake City: University of Utah; 1958. 40. Homola S. Bonesetting, Chiropractic and Cultism. Panama City, FL: Critique Books; 1963. 41. Cohen W. Naturopathy. In: Independent Practitioners Under Medicare: A Report to Congress. Washington, DC: US Department of Health, Education, and Welfare; 1968. 42. The State Licensing of Health Occupations; U.S. Department of Health, Education, and Welfare; and the National Center for Health Statistics Public Health Service Publication No. 1758 (1967) reported: “Naturopaths are specifically licensed in at least five States and the District of Columbia. The absence of a State from this list does not imply that there are no licensed naturopaths. Illinois, for example, could be covered by the medical practice act. Texas and Virginia provide for naturopaths on examining boards but no information is available on licensing practices. Elsewhere licensing powers have been abolished and no new licenses have been issued; for example, in 1965 naturopathic licenses renewed in California numbered 66 and in Florida, 136.” 43. Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol Q. 1992;13:369– 383. 44. Cassedy JH. Medicine in America: A Short History. Baltimore: Johns Hopkins University Press; 1991. 45. Duffy J. From Humors to Medical Science: A History of American Medicine. Urbana, IL: University of Illinois Press; 1993:350. 46. Murphy LR. Enter the Physician: The Transformation of Domestic Medicine, 1760–1860. Tuscaloosa: University of Alabama Press; 1991. 47. Kaufmann M. Homeopathy in America. In: Gevitz N, ed. Other Healers: Unorthodox Medicine in America. Baltimore: Johns Hopkins University Press; 1988:99–123. 48. Hough HJ, Dower C, O’Neil EH. Profile of a Profession: Naturopathic Practice. San Francisco: Center for Health Professions; 2001. 49. Olsen KG. The Encyclopedia of Alternative Health Care. New York: Pocket Books; 1989. 50. Baer HA. Biomedicine and Alternative Healing Systems in America. Madison: University of Wisconsin Press; 2001. 51. Baer HA. The sociopolitical status of U.S. naturopathy at the dawn of the 21st century. Med Anthropol. 2001;15(3):329–346. 52. Pizzorno Jr JP, Bastyr J. The father of modern naturopathic medicine. Integr Med. 2004;3:28–29.

GENERAL BIBLIOGRAPHY Baer HA. Organizational rejuvenation of osteopathy. Soc Sci Med. 1981;15A:701–711. Baer HA. A comparative view of a heterodox system: chiropractic in america and britain. Med Anthropol. 1984;8:151–168. Baer HA. The American dominative medical system as a reflection of social values in the larger society. Soc Sci Med. 1989;28:1103–1112. Barrett S, Herbert V. The Vitamin Pushers: How the Health Food Industry Is Selling America a Bill of Goods. New York: Prometheus Books; 1994. Barrett S, Jarvis W. The Health Robbers: A Close Look at Quackery in America. New York: Prometheus Books; 1993. Berlinger H. A System of Medicine: Philanthropic Foundations in the Flexner Era. New York: Tavistock Publishers; 1985.

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47.e2

References

Berman A, Flannery MA. America’s Botanico-Medical Movements: Vox Populi. Oxford, MS: Pharmaceutical Products Press; 2001. Bloomfield RJ. Naturopathy in traditional medicine and health care coverage. In: Bannerman RH, Burton J, Wen-Chieh C, eds. Traditional Medicine and Health Care Coverage. Geneva: World Health Organization; 1983. Breiger G. Medical America in the 19th century. Baltimore: Johns Hopkins Press; 1972. Cody G. History of naturopathic medicine. In: Pizzorno J, Murray M, eds. Textbook of Natural Medicine. Orlando FL: Churchill Livingstone; 1999:17–40. Coward R. The Whole Truth: The Myth of Alternative Health. London: Faber & Faber; 1989. Duffy J. The Healers. Urbana, IL: University of Illinois Press; 1976. Engel J. Doctors and Reformers. Columbia: University of South Carolina Press; 2001. Farrell JB. Naturopathic legislation and education. Rhode Island Med J. 1945;28:248–263. Fishbein M. The Medical Follies. New York: Boni & Liveright; 1925. Fishbein M. The New Medical Follies. New York: Boni & Liveright; 1925. Fishbein M. Quacks and Quackeries of the Healing Cults. Girard, KS: Haldeman-Julius Publications; 1927. Fishbein M. Fads and Quackery in Healing. New York: Covici, Friede Publishers; 1932. Flannery MA. John Uri Lloyd: The Great American Eclectic. Carbondale: Southern Illinois University Press; 1998. Goodenough J. Dr Goodenough’s Home Cures & Herbal Remedies. New York: Crown; 1982. Gort EH, Coburn D. Naturopathy in Canada: changing relationships to medicine, chiropractic and the state, social science and medicine. Soc Sci Med. 1988;26:1061–1072. Green H. Fit for America: Health, Fitness, Sport & American Society. New York: Pantheon Books; 1986. Griggs B. Green Pharmacy. London: Jill, Norman & Hobhouse; 1981. Haller Jr JS. Medical Protestants: The Eclectics in American Medicine, 1825–1939. Carbondale: Southern Illinois University Press; 1994. Haller Jr JS. Kindly Medicine: Physio-Medicalism in America, 1836–1911. Kent, OH: Kent State University Press; 1997. Haller Jr JS. A Profile in Alternative Medicine: The Eclectic Medical College of Cincinnati, 1845–1942. Kent, OH: Kent State University Press; 1999. Inglis B, West R. Alternative Health Guide. New York: Knopf; 1983. International Society of Naturopathic Physicians Yearbook. Los Angeles: ISNP; 1948. Kaufmann M. Homeopathy in America. In: Gevitz N, ed. Other Healers: Unorthodox Medicine in America. Baltimore: Johns Hopkins University Press; 1988. Kirchfeld F, Boyle W. Nature Doctors: Pioneers in Naturopathic Medicine. Buckeye, OH: Buckeye Naturopathic Press; 1994. Ludmerer K. Learning to Heal. New York: Basic Books; 1985. Manger LN. A History of Medicine. New York: Marcel Dekker; 1992. Maretzki TW. The “Kur” in West Germany. Soc Sci Med. 1987;24:12. Maretzki TW, Seidler E. Biomedicine and naturopathic healing in West Germany: a historical and ethnomedical view of a stormy relationship. Cult Med Soc. 1985;9:383–421. McKeown T. The Role of Medicine: Dream, Mirage, or Nemesis?. London: Nuffield Provincial Hospitals Trust; 1976. Mills D. Study of Chiropractors, Osteopaths and Naturopaths in Canada. Ottawa, Canada: Royal Commission on Health Services; 1966. Rogers N. An Alternative Path: The Making and Remaking of Hahnemann Medical College and Hospital of Philadelphia. New Brunswick, NJ: Rutgers University Press; 1998. Rosenberg C. The Care of Strangers: The Rise of America’s Hospital System. New York: Basic Books; 1987. Rosengren WR. Sociology of Medicine: Diversity, Conflict and Change. New York: Harper & Row; 1980. Roth J. Health Purifiers and Their Enemies: A Study of the Natural Health Movement in the United States. New York: Prodist; 1976. Rothstein W. American Physicians in the 19th century. Baltimore: Johns Hopkins Press; 1972.

Serrentino J. How Natural Remedies Work. Vancouver, BC: Hartley & Marks; 1991. Twaddle AC, Hessler RM. A Sociology of Health. New York: Macmillan; 1977. Twaddle AC, Hessler RM. A Sociology of Health. Rev ed. New York: Macmillan; 1987. Utah Legislative Council Staff. A study of the healing arts with particular emphasis upon naturopathy (a report to the legislature). In: Vollmer HM, Mills DL, eds. Professionalization. Upper Saddle River, NJ: Prentice-Hall; 1958. Wardwell WI. Social Strain and Social Adjustment in the Marginal Role of the Chiropractor (PhD dissertation). Boston: Harvard University; 1951. Wardwell WI. A marginal professional role: the chiropractor. Social Forces. 1952;30:339–348. Wardwell WI. The reduction of strain in a marginal social role. Am J Sociol. 1955;61:16–25. Wardwell WI. Orthodox and unorthodox practitioners: changing relationships and the future status of chiropractors. In: Wallis R, Morley P, eds. Marginal Medicine. London: Peter Cohen; 1976. Wardwell WI. The present and future role of the chiropractor. In: Haldemann S, ed. Modern Developments in Chiropractic. New York: Appleton; 1980:25–41. Wardwell WI. Chiropractors: challengers of medical domination. In: Roth J, ed. Research in the Sociology of Health Care. Greenwich, CT: JAI Press; 1982:207–250. Wardwell WI. Chiropractors. In: Gevitz N, ed. Other Healers: Unorthodox Medicine in America. Baltimore: Johns Hopkins University Press; 1988. Whorton JC. Drugless healing in the 1920s: the therapeutic cult of sanipractic. Pharm Hist. 1985;28:14–25. Wirt A. Health & Healing. New York: Houghton Mifflin; 1983. Wohl S. Medical Industrial Complex. New York: Harmony; 1983.

NATUROPATHIC BIBLIOGRAPHY Abbot JK. Essentials of Medical Electricity. Philadelphia: WB Saunders; 1915. Altman N. The Chiropractic Alternative: How the Chiropractic Health Care System Can Help Keep You Well. Los Angeles: JP Tarcher; 1948. Barber ED. Osteopathy Complete. Kansas City: Private; 1896. Baruch S. An Epitome of Hydro-Therapy. Philadelphia: WB Saunders; 1920. Benjamin H. Everybody’s Guide to Nature Cure. 7th ed. London: Thorsons; 1981. Bennet HC. The Electro-Therapeutic Guide. Lima, OH: National College of Electro-therapeutics; 1912. Bilz FE. The Natural Method of Healing. New York: Bilz, International News; 1898. Dejarnette MB. Technic & Practice of Bloodless Surgery. Nebraska City, NE: Private; 1939. Downing CH. Principles & Practice of Osteopathy. Kansas City: Williams; 1923. Filden JH. Impaired Health (Its Cause & Cure). 2nd ed. Denver: Private; 1921. Finkel H. Health via Nature. New York: Barness Printing & Society for Public Health Education; 1925. Foster AL. Foster’s System of Non-Medicinal Therapy. Chicago: National Publishing Association; 1919. Fuller RC. Alternative Medicine and American Religious Life. New York: Oxford University Press; 1989. Goetz EW. Manual of Osteopathy. Cincinnati: Nature’s Cure; 1909. Gottsschalk FB. Practical Electro-Therapeutics. Hammond. Frank Betz; 1904. Graham RL. Hydro-Hygiene. New York: Thompson-Barlow; 1923. Inglis B. Natural Medicine. London: William Collins; 1979. Johnson AC. Principles & Practice of Drugless Therapeutics. Los Angeles: Chiropractic Education Extension Bureau; 1946. Just A. Return to Nature. Lust B, trans. Butler, NJ: Lust Publications; 1922. Kellogg JF. Rational Hydrotherapy. Battle Creek, MI: Modern Medical Publications; 1901:1902. Kellogg JH. New Dietetics. Battle Creek, MI: Modern Medical Publications; 1923. King FX. Rudolf Steiner and Holistic Medicine. York Beach, MA: Nicolas-Hays; 1987.

References Kuhne L. Neo-Naturopathy (New Science of Healing) Lust B, trans. Butler, NJ: Lust Publications; 1918. Lust B. Universal Directory of Naturopathy. Butler, NJ: Lust Publications; 1918. MacFadden B. Power & Beauty of Superb Womanhood. NJ: Physical Culture Publications; 1901. MacFadden B. Building of Vital Power. New York: Physical Culture Publications; 1904. Murray CH. Practice of Osteopathy. Elgin, IL: Private; 1906. Murray MT, Pizzorno JE. Encyclopedia of Natural Medicine. Rocklin: CA: Prima; 1998. Pizzorno JE. Total Wellness. Rocklin, CA: Prima; 1996.

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Richter JT. Nature—The Healer. Los Angeles: Private; 1949. Spitler HR. Basic Naturopathy. Des Moines: ANA; 1948. Trall RT. Hydropathic Encyclopedia. Vols. 1–3. New York: SR Wells; 1880. Turner RN. Naturopathic Medicine: Treating the Whole Person. London: Thorsons; 1984. Weltmer E. Practice of Suggestive Therapeutics. Nevada, MO: Weltmer Institute; 1913.

4 The History of Naturopathic Medicine

A New and Revisionist Perspective: The Lost Years of the 20th Century George W. Cody, JD, MA

OUTLINE Introduction and Author’s Note, 48 Part One: Who were the Naturopaths?, 49 In the Beginning, 49 Germ Theory and Conventional Medicine, 49 The Early Integrators, 49 The Early 20th Century, 51 Drugless Healing, 51 Benedict Lust, 51 Naturopathy and Chiropractic, 51 Nature Cure and the Vital Force, 52 Genesis of Post–WWI Professionalism, 52 A Short Course in Medical Dominance, 52 A Time to Build a Profession: The 1930s, 53 Dr. Budden and Evolution of the Profession in the Pacific ­Northwest, 53 Robert V. Carroll, ND—Leader of NDs in Washington, 54 Natural Healing at its Peak, 55 A Profession, 56 The Merging of Efforts, 56 Firming Up the Curriculum—Chiropractic and Naturopathy, 57 New Developments in Postwar Scholarship, 57 A.R. Hedges, DC, ND, and W. Martin Bleything, DC, ND—First Connections, 58 The AMA and President Truman, 60 Enter the Class of 1953, 60 More Professional Matters for Dr. Budden, 61 Part Two: What Happened to Them?, 62 Moving On, 62

Headwinds, 62 Revisiting Basic Science, 63 And Scandals, 63 And Repercussions, 64 More Basic Science, 64 Dr. Schlichting, 65 Back to the National Scene, 66 Dr. Schlichting Becomes President, 66 Naturopaths at Their Peak, 67 The Late 1940s and Professional Growth, 67 In Memoriam—Robert V. Carroll, Sr., 67 1947–1950 and Forward, 67 After the Scandals, 68 A Change of Identity, 68 Medical Dominance Arises, 68 The Beginning of the End, 69 The Texas Medical Wars, 69 Back to Education: WSC and Natura Medicina, 69 Back to Texas, 71  The End, 73 The End, Part 2, 74 And Naturopathy Is Finished at WSC, 74 Back to the Texas Medical Wars, 75 Three More States Fall: 1955 to 1957, 76 The Florida Saga Begins, 77 Utah, 78 Washington State Under Siege, 78 A Dismal State of Affairs: The 1960s, 79

INTRODUCTION AND AUTHOR’S NOTE

healing between 1945 and 1975 that this chapter will seek to explore and document—a history that is surprisingly rich and deep. Discovering and documenting the history of this period had to wait until resources became available for research. Five new resources that became available in the past 10 to 15 years are at the heart of this new chapter. All of these resources have become available—accessible for research—due to modern technology. The first is the library resources of the modern naturopathic colleges, primarily Bastyr University and what is today the National University of Natural Medicine (NUNM). These resources, though, have largely not been digitized and required old-fashioned “shoe leather” research.

When earlier chapters on natural healing in the United States were researched and written, the available sources were primarily the extensive publications of Benedict Lust and the works of other historians. When other historians had looked extensively at naturopathy—historians such as James Whorton, Hans Baer, or (recently) Susan Cayleff— they also relied on primarily on Benedict Lust. This has left a historical gap between Lust’s death in 1945 and the 1970s when a modern naturopathic medicine emerged and began making its own historical record. But there is a hidden history of natural

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CHAPTER 4  This work is greatly indebted to the “shoe leather” of Eric Blake, ND, of Portland, Oregon (and to Mitchell Stargrove, ND, also of the Portland area, who introduced this author to Eric’s work). Eric had spent many hours about 15 years ago researching the stacks of material in the NUNM “rare book” room with an eye to what Benedict Lust either did not tell us or any off-track items that were buried in Lust’s publications. This led to many hours of conversation and correspondence between this author and Eric that led down the path of a new historical synthesis. Second, the John Bastyr archives at Bastyr University then opened up material that Dr. Bastyr had saved from this era that had been in boxes, unexplored. Chief among these was a collection (not complete) of the publications of the Western American Naturopathic Association (ANA)/American Naturopathic Physicians and Surgeons Association/ American Association of Naturopathic Physicians from 1947 to 1954. Dr. Bastyr was a protégé of Dr. Robert V. Carroll Sr., who had brought Bastyr into the world and practice of naturopathy, as these records documented. (Thanks are owed to the staff of the library at Bastyr University, especially Jane Saxton and Linda Tally.) Third is the archive materials at the W.A. Budden Library of the University of Western States (UWS) in Portland, Oregon. The UWS is the modern successor to Dr. Budden’s Western States College where Dr. Budden was president from 1929 to 1954. What was not already digitized and accessible on the UWS website was scanned and made available to this author by the archive librarian, Katie Lockwood. She also deserves a large credit for advancing this historical work product. Fourth is two resources on the history of the UWS and of chiropractic: the history of the UWS by Lester Lamm, DC, and the history of chiropractic education by Keating, Rehm, and Callender, which includes the detailed minutes of the Council on Education of National Chiropractic Association, within which Dr. Budden participated, operated, and influenced.1 Fifth, and finally, a massive amount of newspaper archive material has been digitized and made available. Coupled with search-engine capacities, a completely buried panorama of natural healing history has gone through a supernova process. Armed with these voluminous materials, the questions “Who were the naturopaths?” and “What happened to them?” can at last start to be answered. Editors’ Note: This is the second of two chapters documenting the origins and evolution of naturopathic medicine. Although these were written to stand alone, a full understanding requires reading both chapters. 

PART ONE: WHO WERE THE NATUROPATHS? Natural healing advanced a science-based alternative to the American medical profession of the 20th century; this alternative philosophy started first as naturopathy as promulgated by Benedict Lust, and then its concepts and practice evolved into naturopathic medicine primarily through the work of three early pioneers: Henry Lindlahr, William C. Schulze, and Walter B. Cannon, all medical doctors disenchanted by conventional medicine moving in what they considered the wrong direction. By the early 1950s, natural healing—an alternative to conventional medicine practiced by chiropractors and naturopaths—reached its peak. Practitioners were spread across the United States, and their common philosophy was based on a belief in the vital force—the inherent healing power within all of us. The leadership of W.A. Budden and Robert V. Carroll was critical to the professional growth of natural healing from the mid-1930s to the early 1950s. They led a professionalization movement within natural healing that brought these practitioners to the peak that was reached in the post-WWII United States. 

IN THE BEGINNING In the early 20th century there was medicine as practiced by medical doctors (“MDs”) and as represented in the United States by the American

The History of Naturopathic Medicine

49

Medical Association (AMA). The AMA became, over the first 75 years of the 20th century, one of the most powerful political interest groups in US history and became known as “organized medicine.”2 There were alternatives that emerged early in the 20th century, primarily in the form of chiropractic, naturopathy, and other “drugless’ schools of healing as well as in the work of MDs who diverged from the AMA’s concept of “scientific medicine.” Scientific medicine was based on Louis Pasteur’s “germ theory.”

Germ Theory and Conventional Medicine At the turn of the 20th century, as Howard Berliner (1985) has documented, straight germ theory (germ x causes disease y) became established as the core concept of “scientific medicine” in American allopathic medical education. At the time, the major rivalry in American medicine was between allopaths (about 60% of medical practitioners) and homeopaths (about 30%, the balance being Eclectics and physio-medicalists). Once the substantial resources of the Rockefeller philanthropies were put behind scientific medical education based on germ theory— with the full consent of the AMA—American medicine became synonymous with the germ theory. This, the Flexner Report (1910), and medical research devoted to finding pharmaceuticals to defeat germs to “cure” disease were all funded by Rockefeller philanthropies and led to what is considered to be the dominant paradigm in American medicine.3 As Berliner documents, this was largely the result of a determination to put the Rockefeller philanthropic resources behind this concept of “scientific medicine” not, at the time, any clear clinical superiority on the part of the allopathic philosophy. As of the period in which this took place, largely 1900 to 1920, there was no clinical validation for scientific medicine in terms of the discovery of specific pharmaceuticals of demonstrated efficacy.

Be’champ, Bernard, and the Alternatives to Germ Theory The concept of an alternative to the germ theory of disease traces to two French contemporaries of Louis Pasteur: Augustine Be’champ and Claude Bernard. Pasteur’s work asserting microbes as the cause of disease has been well documented and lauded and does not need to be reproduced here. Be’champ’s theory was, put as simply as possible in the biological sense, that “germs” are always present in our environment and do not “cause” disease. Disease is related, rather, to the physiology of the host, the human (or mammalian) body, not to the germs per se. What we observe in microbiology relative to disease is the resultant by-product of the body’s failed attempt to reject a pathogenic microbe, a function that a healthy body’s autoimmune system should accomplish.4 Bernard’s work in physiology was much celebrated in the 19th century. As noted by Charles Gross (1998): “Today the fame of Claude Bernard rests primarily (if not entirely) on his idea that the maintenance of the stability of the internal environment (milieu interieur) is a prerequisite for the development of a complex nervous system.” But as noted by Gross and others, although Bernard advanced this idea between 1854 and his death in 1874, it “had no impact for over 50 years after its formulation.” Why did this “insight that the ‘constancy of the internal environment is the condition for the free life’ (have) no significance (indeed no meaning) for biologists for more than 50 years?” One major reason was that “Pasteur’s new bacteriology and its omnipresent, omnipotent germs, were dominating the biomedical Zeitgeist.”5 

The Early Integrators In the pre-WWII years, the work of three MDs that diverged from germ-theory orthodoxy became central to the emergence of integrative medicine. These three MDs are Henry Lindlahr, William Charles Schulze, and Walter B. Cannon.

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SECTION 1 

Philosophy of Natural Medicine

Henry Lindlahr and Integration in Clinical Practice The standard biography of Lindlahr is that of Kirchfeld and Boyle in Nature Doctors.6 His own therapeutic philosophy is set out in his four-volume work Natural Therapeutics, published in 1923 and republished in 1975 as edited by Jocelyn Proby, DO.7 The four volumes are Philosophy, Practice, Dietetics, and Iridiagnosis. Lindlahr started his own school in Chicago in 1914 and built a substantial sanitarium, clinic, and college operation as well.8 A central tenet of Lindlahr’s work, in spite of his medical training, was that the allopathic approach to healing was wrong. There were, he said, “two principal methods of treating disease. One is the combative, the other the preventive… The slogan of modern medical science is, ‘Kill the germ and cure the disease’… The combative method fights disease with disease, poison with poison, and germs with germs.”9 On the other hand, “The preventive method does not wait until disease is fully developed and gained ascendancy in the body, but concentrates its best endeavors on preventing, by hygienic living and natural methods of treatment, the development of disease.”10 In Philosophy, he states: “It is the intent of this volume to warn against the exploitation of destructive combative methods to the neglect of preventive constructive and conservative methods. If these teachings contribute something toward this end they will have fulfilled their mission.” His work is consistent with Walter Cannon’s physiological insights, and a decade before Cannon’s Wisdom of the Body was published, he wrote in Philosophy: The diet expert, the hydrotherapist, the physical culturist, the adjuster of the spine, the mental healer and the Christian Scientist, pay little attention to the pathological conditions or the symptoms of disease. Each of these, in accordance with his theory of disease and cure, regulates the diet and habits of living on a natural basis, promotes elimination, teaches correct breathing and wholesome exercise, corrects the mechanical lesions of the body, or establishes the right mental and emotional attitude, and, in so far as he succeeds in doing this, builds health and so diminishes the possibility of disease. The successful doctor of the future will have to fall in line with the procession and do more teaching than prescribing.11 Lindlahr strongly advocated for Be’champ’s theories, especially in his Philosophy volume. He had discovered Be’champ’s work, he said, through the earliest work of Ethel Douglas Hume.12 Specifically, Lindlahr noted that he had then “made a careful study of [Be’champ’s] last work, entitled The Blood, in which he summarizes the mycrozymian theory of cell life.” From this study, Lindlahr found “a rational, scientific explanation of the origin, growth and life activities of germs and of the normal living cells of vegetable, animal and human bodies.”13 At two points in Philosophy, Lindlahr discusses at length the understanding of Be’champ’s work that he has gained from his own intense study of Be’champ’s writings and how from his own clinical observations and experience, and from Be’champ’s work, he comes to advance three primary manifestations of disease. These manifestations of disease are (1) lowered vitality (vitality is the body’s strength of positive resistance and recuperative power, the “vital force” of cellular function); (2) abnormal composition of blood and lymph; and (3) accumulation of waste, morbid matter, and poisons in the system.14 

William Charles Schulze and Integration in Medical Education Schulze was an MD (of Rush Medical College) who, in 1914, purchased the National School of Chiropractic and broadened its curriculum to include the basic sciences as well as “physiological therapeutics” and mechano-therapy.15 The name was changed in 1920 to the National College of Chiropractic (NCC). His most enduring influence may have come from acquiring and merging Lindlahr’s school after Lindlahr’s untimely passing in 1924 and in his mentoring influences on W.A. (Alfred) Budden, DC,

ND, of Portland’s Western States College and, later on, Joseph Janse, DC, ND, the postwar president of National College (1945–1983).16 As Keating and Rehm noted about Schulze: Part of the Schulze legacy is the tradition of broad-scope, “rational chiropractic,” or what Palmer called “mixing.” As an MD, Schulze had been trained in medical and presumably some minor surgical procedures, but he had apparently committed himself to “drugless healing” early in his career. However, drugless healing, which involved a variety of naturopathic methods, was anathema to the Palmer branch of the profession. The physician-chiropractor would quickly run afoul of the adiagnostic, nontherapeutic, subluxation-only forces in the profession.17 Schulze sought “to promote a professionalism among students and doctors which could rival that of medical competitors,” and under Schulze, the NCC introduced laboratory courses in pathology, biochemistry, bacteriology, and toxicology, together with a “strong commitment to diagnostic training,” all in response to the adoption in the late 1920s of the Basic Science Law. The NCC adopted the motto “four ways to beat the basic science law”: (1) Study basic science. (2) Study basic science. (3) Study basic science. (4) Study basic science. Schulze came under much criticism from the “straights” in chiropractic, and this only increased after he purchased the Lindlahr School of Natural Therapeutics from Henry Lindlahr’s estate and transferred “the entire student body and the better part of the faculty” to the NCC.18 In 1928 this part of the National school was formed into the National College of Drugless Physicians, which was National’s ND degree program. The National College of Chiropractic Journal became a voice that extended beyond the NCC itself by the early 1920s, becoming a professional voice as well, challenging B.J. Palmer’s “straight” chiropractic philosophy as well as the antagonism of Morris Fishbein, MD, the editor of the Journal of the American Medical Association (JAMA). This voice was first found under the NCC secretary, A.J. Forster, MD, DC, and then “under the editorship of William Alfred Budden, DC, ND, an English immigrant and former economics instructor at the University of Alberta who graduated from the NCC in 1923.”19 From the mid-1920s, Schulze was involved more in the professional activities than in the day-to-day operations of the NCC, and always in the “mixer” camp—first in the American Chiropractic Association (ACA) and then starting in 1930 in the successor National Chiropractic (NCA). Schulze then followed a busy, nationwide speaking schedule in the early 1930s, advocating consistently for the broad-scope professional values of the NCA as taught at the NCC/NCDP. At the 1934 annual meeting of the NCA (May 1934), Schulze—a regular speaker at these annual meetings—noted in his speech that at the time, “harmony among Chiropractors and Drugless practitioners, especially the Naturopaths, was good to look upon.”20 In 1934 Dr. Schulze joined a convention tour coined “the Northwest Circuit” organized by C.O. Watkins, DC, of Montana that had its speakers speak at NCA-affiliated conventions held in Minnesota, North Dakota, Montana, Washington, British Columbia, Idaho, Utah, Wyoming, and Colorado. The Washington stop was for the meeting of the Northwest Chiropractors Association and was a gathering of 300 attendees from Oregon, Washington, Idaho, Northern California, and British Columbia in September.21 The last full year that Dr. Schulze was actively engaged was 1934; he was in ill health for much of 1935 and passed away in September 1936. When he passed away, one of the very many appreciation letters honoring his productive life was sent by Dr. Robert Carrol as the president of the Washington State Naturopathic Association, saying, “The entire drugless profession has lost a friend and teacher.”22 In 2002 Rehm and Keating noted as Dr. Schulze’s great accomplishment, “Schulze created an intellectual environment that would be

CHAPTER 4  rivalled in the middle age of the profession only at Budden’s Western States College.”23 

Walter B. Cannon and Integration in Medical Research Cannon did extensive research in physiology, his area of teaching at Harvard. He concurred with Bernard’s concept of the “internal environment” of the human body and coined the term homeostasis to describe the body’s need to respond physiologically to the external environment to maintain a stable internal environment, which he described as a primary function of the central nervous system.24 His concept was that through what he called the “wisdom of the body,” mammalian forms such as the human body “may be confronted by dangerous conditions in the outer world and by equally dangerous possibilities within the body, and yet continue to live and carry their functions with relatively little disturbance,” something that Hippocrates had called vis medicatrix naturae. In a distinctive passage in The Wisdom of the Body, Cannon set forth a concept that became central to the postwar chiropractor-naturopaths: The fathers of medicine made use of an expression, “the healing forces of nature,” the vis medicatrix naturae. It indicates, of course, recognition of the fact that processes of repair after injury, and of restoration to health after disease, go on quite independent of any treatment that the physician may give … In the first place, the well-trained physician is acquainted with the possibilities and limitations of self-regulation and self-repair in the body. He is instructed in that knowledge and employs it not only for his own intelligent action but also as a means of encouragement for the patient who looks to him for counsel … Again, the physician realizes better than the layman that many of the remarkable capacities of the organism for self-adjustment require time—all of the processes of repair belong in that class—and that they can play an important role in restoring the organism to efficiency only if they are given the chance that time provides … Furthermore the physician realizes that he has at his command therapeutic with which he can support or replace the physiological self-righting or self-protective processes we have been considering … Finally a great service which the physician renders is the bringing of hope and good cheer to his patients. He has seen at work in many cases the restorative processes of the organism … When we are afflicted and our bodily resources seem low, we should think of these powers of protection and healing which are ready to work for the bodily welfare.25 Lindlahr was the greatest direct influence on the post-WWII philosophy of natural therapeutics, the central core of “drugless” or “nonmedical” philosophy. Lindlahr’s and Cannon’s work have a remarkable consistency between them, although Lindlahr was largely influenced by Be’champ and Cannon by Bernard. Together they advanced the work of these two 19th-century French scientists into the 20th century, and in doing so, they advanced a scientific basis for an “alternative” to the germ theory that was at the core of conventional “scientific medicine.” Schulze pioneered the education of physicians in a professional “drugless” therapeutics consistent with the theoretical work of Lindlahr and Cannon. 

THE EARLY 20TH CENTURY The shaping of America’s modern healthcare landscape began in what historians call the Progressive Era—roughly 1900 through the end of World War II in 1919. At the turn of the 20th century, the AMA had begun the elevation of allopaths over homeopaths and Eclectic

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physicians—all MDs—and had completed this process by the end of the Progressive Era, aided by the 1910 Flexner Report and the efforts of the Rockefeller and Carnegie Foundations (see previous discussion). By the early 1920s, what had become the AMA’s monopoly structure within the medical profession was in place.26

Drugless Healing But as homeopaths and eclectics disappeared, a wide range of practitioners known as “drugless healers” emerged. In this period the licensing structure that became a critical part of the AMA’s monopoly structure had not been fully adopted across the United States, and these drugless healers, probably several thousand of them, were to be found in practice. The practitioners of manipulation modalities— including osteopaths and chiropractors, but others as well, such as mechanotherapists and naprapaths—were “drugless.” So were myriad others, including practitioners of neuropathy, physcultopathy (physical culture), sanipractic, food science, suggestive therapeutics, and Swedish movement. Some of these drugless healing practitioners were specifically regional; naprapaths were almost exclusively found in Illinois, where D.J. Palmer protégé Simon Oakley had founded his school, and sanipractors were originally exclusive to the state of Washington before advancing their presence into British Columbia in Canada.27 

Benedict Lust In 1902 Lust originated his use of the term naturopathy and began his development of a theory and philosophy of health and healing “to describe the eclectic compilation of doctrines of natural healing that he envisioned was to be the future of natural medicine.” Lust launched his career as the progenitor of naturopathy, adopting that name for his eclectic brand of natural therapeutics and placing the term naturopath firmly in the title of his monthly publications, which continued under his status as editor and publisher until his death in 1945.28 One of the anomalies of Lust’s work was that for at least 30 years, there was no firm definition of naturopathy; rather, Lust clearly attempted to incorporate all methods of “drugless healing” and “natural therapeutics” into his philosophy of naturopathy. This included the original concept of osteopathy devised by Dr. Still and chiropractic as devised by D.D. Palmer. In Lust’s view, these were all pieces of naturopathy, linked together by not being “allopathic medicine.”29 This “drugless” label could only incorporate Still’s osteopathy in its original form, which did not incorporate a materia medica, as described, for instance, in Charles Hazzard’s Principles of Osteopathy (3rd edition, 1899).30 Where chiropractic was concerned, Lust’s naturopathy became clearly allied with the “mixer” philosophy, and both Lust and the mixers were in conflict at the time with the “straights” led by B.J. Palmer.31 

Naturopathy and Chiropractic Precisely when chiropractic and naturopathy first became melded into a symbiotic relationship is historically murky. D.D. Palmer did not—at least as historically reported—practice or teach naturopathy or openly associate himself with it. His son, B.J., was adamantly opposed to anything that would dilute the purity of “straight” chiropractic. Benedict Lust, the historical progenitor of naturopathy in America, taught and endorsed chiropractic very early in the 20th century, but it was Solon Langworthy, an early student of D.D.’s, who opened the second identifiable school of chiropractic in 1903 and based its curriculum on mixing nature cure with chiropractic. Palmer was the originator of chiropractic, of course, but he adopted a kind of “Johnny Appleseed” approach to his spinal manipulation insights, “planting” the concept of chiropractic adjustment more than

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anything else. He was traveling constantly after 1902 and granting the right to practice and to educate others in his methods to recipients of his written “diplomas.” It was B.J. Palmer, the son, who adopted a proprietary interest in chiropractic after his graduation from D.D.’s instruction in 1902, much as Lust did in naturopathy. Both chiropractic and naturopathy could best be described as social movements in the field of health and healing in their first two decades of evolution. It was not until the 1920s that others began to work at the professionalization of chiropractic and naturopathy, and many of the most influential of these who became connected with naturopathy were chiropractic “mixers,” becoming known in time as the chiropractor-naturopaths or “DC, NDs.” 

Nature Cure and the Vital Force Benedict Lust’s vision of drugless healing, although it continued to “expand,” as noted by Susan Cayleff, was always intended to be consistent with Germanic 19th-century “nature cure.” As noted by Henry Lindlahr is his 1915 book Nature Cure, the original concepts were credited to Vincent Preissnitz.32 As noted by Lindlahr, nature cure became “the idea of drugless healing [which] spread over Germany and over the civilized world.”33 Citing Lindlahr, Susan Cayleff summarized American nature cure’s idea of human sickness this way: Henry Lindlahr, MD, a leader in naturopathic philosophy, explained the five specific conditions that caused disease; lowered vitality; abnormal composition of blood and lymph, resulting mainly from wrong eating and drinking; accumulation of waste, producing morbid matter and poison in one’s system; mechanical lesions, that is pressure, tension or strain on nerves and nerve centers caused by luxations (dislocations) of bony structures or straining of muscles and ligaments; and discordant or destructive mental and emotional attitude. These conditions more or less remained the core of naturopathy for decades.34 Treatment by means of nature cure theory relied on the body’s own drive to maintain health—to achieve what Walter Cannon later called “homeostasis”—by recognition of what was labeled the “vital force.” The work of F.E. Bilz, a German MD, was very influential in this regard. Bilz first published his synthesis of German nature cure in Germany in 1898, and in 1901 he published Natural Method of Healing: A Complete Guide to Health (translated from the latest German edition) as the English language version of his work.35 Bilz noted: “[I]t is known that we cannot heal a disease with the remedy we apply, but that it is the vital force within us which heals, and that we need but aid it, [and] our position becomes a far easier one.”36 This “vital power,” the “power of healing,” Bilz said, “resides in man himself … divine nature placed it there at the creation of each being.’’ Adopting this concept, Lindlahr noted that all healing must “economize vital force” because it is the vital force that “is the Supreme power and intelligence, acting in and through every atom, molecule and cell in the human body which is the true healer, the vis medicatrix nature which always endeavors to repair, to heal and to restore …”37 

GENESIS OF POST–WWI PROFESSIONALISM To understand the DC, NDs and their professionalization requires going beyond the career of Benedict Lust and the natural living and healing movement that he founded. It also requires more historical background. The committed professionalization process that followed began in the late 1920s and continued through the first years after WWII. The focus was on moving the educational process and the clinical

practice of both naturopathy and chiropractic past the “founder’s grip” of Benedict Lust and B.J. Palmer by means of the creation of stable residential colleges and stable state and national professional organizations. This task was compounded with regard to both of these professions by the committed drive by organized medicine in the United States (primarily in the form of the AMA and its state and local constituencies) toward medical dominance. To respond to the determination of medicine to achieve this dominance, a resistance based on the core values of “Americanism” was required, along with personal resilience and tenacity.

A Short Course in Medical Dominance Medical dominance is best understood by reference to the book of this same name by Australian sociologist Evan Willis.38 The subject can be supplemented by a very useful work by another sociologist, Saul Rosenthal, A Sociology of Chiropractic.39 These sociologists argue that organized medicine has had as a goal since at least 1900 the achievement of medical dominance in domains: achievement of complete control over its own work (autonomy), achievement of complete control over the work of others in health care (dominion), and achievement of complete control over all matters of public policy within the health domain (medical sovereignty). Willis’s argument is sophisticated and extensive; indeed, his discussion of the subject is a book-length treatise. But the short version as it relates to the “exclusion” of “alternative” practices like chiropractic and naturopathy can be summarized. Relying on earlier work by Howard Berliner and others, he demonstrates that medicine’s dominance was achieved through the allopathic claiming of the mantle of “science” for its work. This was done through the adoption of the germ theory of disease.40 This, in turn, had two advantages, as Willis argues: first, individual clinical skill became less important than extensive schooling within a laboratory and hospital-based system (“clinical skill” versus “clinical science”), and second, health became an individual scientific problem, not a social, environmental or lifestyle problem.

The “Great Trade” In the United States, this manifested itself in the early 20th century as “the Great Trade” described by Fredric Wolinsky: “[B]y 1925, the AMA had gained a monopoly over the production and licensing of physicians. This included the power to determine what the curriculum should be, how many students should be admitted, which students should be admitted, and how many faculty there should be for each student. Thus 1910 marked a trade of importance between society (as represented by state and federal governments) and the AMA. The trade gave the AMA the exclusive right and sole power to regulate the medical profession. In return, the AMA was to give society the best and most efficient medical care system possible. Society has clearly lived up to its part of the bargain …”41 

American Exceptionalism “American exceptionalism” or “Americanism” has been analyzed extensively in the book of the same name by Professor Seymour Martin Lipset, one of the most distinguished US academicians. Professor Lipset gives this synopsis of Americanism: “The American Creed can be described in five terms: liberty, egalitarianism, individualism, populism and laissez-faire.”42 Medical dominance strikes at each of these five values, all in the name of “scientific medicine.” It is based on using the power of the state to enforce the “great trade” as public policy, the antithesis of populism. It is corporatist, not individualist and laissez-faire. It creates a

CHAPTER 4  favored class of medical professionals over serving egalitarianism, and by the exercise of the power of the state, it constrains the liberty of the patient as a consumer. 

A Time to Build a Profession: The 1930s The drugless healing concepts of nature cure became, by the 1930s, the philosophical basis for a professional alternative to conventional medicine in the form of the chiropractor-naturopaths, the “DC, NDs.” By the mid-1930s, as Susan Cayleff notes, Benedict Lust came to abandon “therapeutic inclusivity” and declared that a clear and fixed professional identity was necessary.43 For some others who had already formed a professional identity and founded schools and colleges, this moment of self-reckoning came not a moment too soon. It was time to bring all of this into focus as a professional identity once and for all.

The Move Toward Professionalization By the 1930s, the concept of “drugless healing” began to change, and significantly. The majority within osteopathy was moving to add materia medica to osteopathic manipulation and prescribing in line with allopathic thinking and the germ theory.44 The majority within chiropractic were “mixers,” perhaps 70% of chiropractors.45 And within naturopathy, the amalgamation period of the previous 30 years was giving way to identification as naturopaths and abandonment of other drugless labels.46 In the case of osteopathy, the conflict between the originalists and the modernists played out within the American Osteopathic Association (AOA) in the form of battles over “standards” applicable to the osteopathic colleges. Among chiropractors, two professional associations emerged by the early 1930s, the National Chiropractic Association (NCA), which was the association for the “mixers” within chiropractic, and the B.J. Palmer–led Chiropractic Health Bureau, which in 1941 became the International Chiropractic Association—the organization of the “straights.” From the AMA’s perspective, the “straights” were the most easily labeled as a “healing cult.” The straights stood politically for 18-month schooling directed toward identifying “subluxations” of the spine and resolution by manual spinal adjustment as the treatment for all human ailments. A high school education was considered sufficient as a prerequisite for a “straight” chiropractic education. The NCA had adopted a 4-year residency education requirement by the end of the 1930s, led by the Metropolitan Chiropractic College, Western States College (WSC or Western States) and the National Chiropractic College. A leader in consistently upgrading educational standards within the NCA was W.A. Budden of Western States. Within naturopathy, the transition in the 1930s was more complex. As pointed out by Susan Cayleff, by 1935 Benedict Lust moved away from considering all drugless healers part of naturopathy, regardless of how they identified themselves. After three decades, he instead declared that all naturopaths needed to identify as such, encouraging all remaining drugless healers to openly join the naturopathic movement.47 Kirchfeld and Boyle assert that Lust had gone beyond the establishment and popularization of the American naturopathic movement by the end of the 1920s and “must be credited with four other accomplishments.” These were founding the American School of Naturopathy, founding the ANA, his publications, and “the legal status of naturopathy attained as a result of his efforts,” which they call “the most tangible of his efforts.” They note that “it is difficult to separate the success of Lust’s organizations from that of his publications.”48 By the early 1930s, the success of Lust’s efforts must be deemed “qualified.” A 1927 survey by a committee of the AMA of all “schools of chiropractic and naturopathy” found Lust’s combined American School

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of Chiropractic and American School of Naturopathy to be a night school program operating classes for 3 hours each weeknight for a 4-year, 9-months-per-year course. No catalog was published due to expense, but the school was described in Lust’s monthly publications. The school as of 1927 and forward was not established to function in the era of the Basic Science Law, and moreover, neither chiropractic nor naturopathy was licensed in New York. In 1935 Lust was found guilty of illegally (under New York law) issuing diplomas awarding a “doctor” degree without a lawful state charter. It is true that Lust’s ongoing influence was from his publications and from his continued popularization of naturopathy through his travels and his speeches. Through this popularization, others were able to obtain legal status for naturopaths in several states, but this was largely accomplished by others in the movement. Lust’s own operations were in New York (school and publications), New Jersey (his first Yungborn Sanitarium) and Florida (second Yungborn Sanitarium). Of these states, only Florida granted naturopaths recognized legal status, and this was accomplished by others in the movement. By the 1930s, an alternate vision formed within the ANS and within some of the NCA schools that offered ND degrees in addition to DC degrees. As Lust’s influence declined during WWII and after his passing in 1945, others came forward with a competing vision of the relationship between chiropractic and naturopathy, of naturopathic education, and of nonmedical clinical practice. How this came about is a piece of history that has not been well documented before. The story centers on a few men and women, the most prominent of whom are W.A. (Alfred) Budden of Western States College, with its Schools of Chiropractic and Naturopathy, and Robert V. Carroll of the ANA. 

Dr. Budden and Evolution of the Profession in the Pacific Northwest Budden’s Early Career and Arrival in Oregon

W.A. Budden, DC, ND, educated at Schulze’s National College and later a Pacific Northwest (NW) transplant, was a leader in the professional development movement of drugless physicians. Over time, Budden acquired several staunch allies in this effort. The alliance of DCs and NDs in the Pacific NW began through the efforts of Dr. Budden and took root during the remarkable Oregon ballot campaign of 1934. This alliance continued to grow in the aftermath of the ballot fight, as Dr. Budden lived by what he considered to be the lessons of this formative campaign. This ballot campaign of 1934 was Dr. Budden’s brainchild. Budden himself had come west from Chicago to Portland, Oregon, steeped in a “mixer’s” amalgam of core chiropractic, physiotherapy, and Lindlahr’s natural therapeutics. Budden attended Schulze’s National College from 1922 to 1924. Upon graduation as a DC, he joined the faculty and in 1925 succeeded the college’s previous dean and school journal editor.49 It was at this time that National purchased and absorbed Lindlahr’s College of Natural Therapeutics, the premier drugless school of the time. Budden was integrally involved in the integration of the Lindlahr programs into national as the college’s ND degree program. As an educator and administrator at National through the 1920s, Budden also authored a textbook for use at National: Physiotherapy: Technique and Treatment.50 In 1929 Budden moved to Portland, and his career as an educator began in earnest. When Budden arrived in Portland in 1928, he purchased the Pacific Chiropractic College for cash; in 1933 the Pacific College was reincorporated and renamed the Western States College. Western States’ core mission was “for the purpose of operating a college that would offer

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DC and ND degrees together with training nurses and health technicians and maintain clinics and hospitals.”51 When he arrived, Budden also networked with both Oregon’s chiropractors and naturopaths. Chiropractic had been licensed first in Oregon in 1915; licensure for naturopathy was more recently established, in 1927.52 He spoke at the Oregon Chiropractic Association’s 22nd Annual Meeting in July of 1929, and then in July of 1930, he spoke at the annual meetings of both the Oregon Chiropractic Association and the Oregon Naturopathic Association. These speaking appearances became a tradition carried out many times with each group over the years until his death in 1954.53 Oregon adopted a Basic Science Law in 1933.54 Dr. Budden’s initial view was that the Basic Science Law was the medical profession’s creation intended specifically to blunt the rise of any competition to MDs, specifically that of DOs, DCs, and NDs. But Budden’s first effort was to try to craft a political response to a political problem. As Budden later related the history of this effort, “October, 1933, saw the formulation of a joint legislative committee to manage the drafting of and the campaign for an amendment to the constitution of Oregon regulating the practice of the healing arts.” The Joint Legislative Committee (JLC) was the joint committee of the Oregon Association of Chiropractic Physicians and the Oregon Naturopathic Association, and as Dr. Budden described, it was “composed of an equal number of chiropractors and naturopaths.”55 The first action of the JLC was to work with legal counsel to draft what became known as the “Healing Arts Amendment,” a proposed amendment to the Oregon Constitution by citizen’s initiative.56 As the news report in The Oregonian, Portland’s and Oregon’s largest newspaper, reported, “petitions for this measure contained approximately 47,000 signatures against the 26,667 required by law. The completed petitions were brought to Salem [Oregon’s capital] by a caravan of 14 automobiles.”57 On Election Day, after an exhaustive 6-month effort, the ballot measure went down by a 3-to-1 margin. This attempt to curtail medical dominance in Oregon was, on the surface, not successful. Nonetheless, Dr. Budden, over time, took heart from what he considered to be the “lessons learned” from the campaign.58 Moreover, he gained some considerable respect for his willingness to engage in politics and the tenacity with which he could wage a political campaign even with limited resources, and this would be to his advantage over the years.59 These were lessons that he seemed to take to heart and that animated him for the next 20 years of his career as an educator and a consummate professional. From these “lessons learned,” Dr. Budden committed himself to several things. He accepted the basic sciences as a necessary part of a “nonmedical” physician’s education, although he continued to argue that professional examinations were best given to candidates by each profession’s licensing board. He actually, in time, came to view the Oregon examinations as quite fairly conducted, and his students gained a high passing rate as the curriculum focused on these subjects as part of the core education in both chiropractic and naturopathy.60 He continued an extensive public-speaking schedule, regularly appearing through the 1930s, the war years, and in the postwar era before lay audiences like the HEL and the Biochemistry League as well as holding speaking events at Western States and giving weekly radio talks. He continued at all times to commit his WSC programs to provide a sound and thorough education to his students in both the School of Chiropractic and the School of Naturopathy. He worked

tirelessly to improve the standards for all similar colleges and took the lead at every turn in increasing the coursework and prerequisites required.61 These alliances and friendships were important to the WSC and to professional development in the Pacific NW. Dr. Budden, and his DC, ND allies, built stability into the education and organization of chiropractic and naturopathy, especially in the western United States and the Pacific NW, but much of their work is forgotten today. One of these alliances will be discussed here as part of Dr. Budden’s efforts to secure strength and stability for both chiropractic and naturopathy in the Pacific NW and at WSC: that with Robert Carroll, DO, ND, of Seattle. 

Robert V. Carroll, ND—Leader of NDs in Washington One of the strongest leaders and professional organizers in his own right was Robert V. Carroll Sr., DO, ND. Dr. Carroll had built the naturopathic profession in Washington. Licensing in Washington was granted under the Drugless Healing Act of 1919. Licenses were actually issued for the practice of sanipractic, a drugless school unique to Washington.62 But Carroll, although his license said “Sanipractic,” was determined to build a distinct identity professionally and allied early with Benedict Lust’s ANA.63 Robert V. Carroll (Sr.) was also educated in Chicago after WW I, graduating from the American College of Osteopathy and the Lindlahr College of Natural Therapeutics (both Lindlahr schools) in 1923. Carroll finished his studies with Lindlahr and his school faculties just a year before Lindlahr’s sudden death from an infection in late March of 1924. Lindlahr’s signature is on Carroll’s Doctor of Natural Therapeutics diploma,64 and Carroll spoke often in later years of having been a student of Lindlahr himself. Carroll moved west to Washington right after graduation, stopping for a year to practice with his brother, O.G., in Spokane before moving on to Seattle.65 By 1930 he had begun the process of professional organization in Washington, founding the Washington Association of Drugless Physicians and serving as its president for 8 years, with the organization’s name changing to the Washington State Naturopathic Association in 1934.66

The Beginning of the Budden–Carroll Alliance The complete origin of Carroll’s association with Dr. Budden and his support for Western States is unclear. Both Drs. Carroll and Budden studied in Chicago at about the same time. Dr. Budden made an alliance with the DCs and NDs in Oregon in the early 1930s and as a leader in the drugless professions in Washington. Dr. Carroll had his own connections with the Oregon NDs. Yet still, any connection that they had before the 1934 Ballot Campaign is not yet documented. But in the immediate aftermath of the campaign, they joined forces, as reported by Benedict Lust. In February 1935, the same month that the Chiropractic Journal published Dr. Budden’s “Medical Propaganda” article detailing B.J. Palmer’s efforts to defeat the Oregon Ballot Campaign, Lust used his “Dr. Lust Speaking” platform in the Naturopath and Herald of Health67 to similarly interfere in professional efforts in the Pacific Northwest (subtitled “Schisms”): Word has come to us of a meeting that was called for Portland, Ore., in December last for the purpose of the “unification and coordination of Naturopathy and Chiropractic.” This went out on the letterhead of the Washington Naturopathic Association with headquarters in Seattle and was signed by the president, Dr. Robert V. Carroll.

CHAPTER 4  Another letter from the Western States College of Portland signed by Dr. A. Budden, calls for a meeting to be held in Seattle on January 12th to put the “finishing touches” on an organization to be known as the International non-Medical Alliance. Let us say right here and now that we are against any alliance between Naturopaths and Chiropractors. (Naturopath and Herald of Health, February 1935, p. 34) Lust went on to say that alliances with the chiropractors in California and elsewhere had helped chiropractors and hurt naturopaths and that furthermore, there should only be the ANA to speak for naturopaths and no other associations or groups that purport to represent naturopaths. “We have no fault to find with Dr. Carroll or Dr. Budden. We are however utterly opposed to the formation of other organizations that would usurp the prerogatives and program of the A.N.A. This organization has stood the test of time.” 

NATURAL HEALING AT ITS PEAK In March 1952 Henry J. Schlichting Jr., ND, appeared before the 42nd annual convention of the Oregon Association of Naturopathic Physicians in Portland, Oregon. At the time, Schlichting was the president of the American Naturopathic Physicians and Surgeons Association (ANPSA).68 Schlichting was quoted as saying that two major national issues facing naturopaths were that alternative schools got no tax support and that naturopaths could not be admitted to tax-supported hospitals. This created “a heavy demand on our profession and the lay public to meet rising … costs.” Schlichting was reported to have told the convention, “Despite these problems the profession ‘is making definite progress on a national scale as evidenced by licensing in over 20 states,’ [and] insurance companies are recognizing naturopaths ‘because they are getting satisfactory results.’”69 Although the “licensing in over 20 states” was a generous count, there was no question that at the time Schlichting was speaking, the natural healing alternative was at its peak. Schlichting was from Midlands, Texas, a West Texas city where all major oil companies had a presence in a state where there were almost 500 licensed naturopaths.70 Specific licensing of naturopathy was in place in 8 states (out of 48); 2 states had naturopaths practicing under drugless licensing, and about a dozen other states had broad, “mixer” licensing of chiropractors. In other states, naturopaths were fairly openly practicing without licensing but consistently pursuing legislation. Natural healers were practicing in about 40 of the 48 states.71

What Is the Vital Force? What bound this natural healing profession together was a belief in the vital force and a resistance to “suppressive drugs,” those pharmaceuticals that relieved symptoms without treating the underlying disease state. Between the mid-1930s and the early 1950s—separate from Benedict Lust and his publications—this doctrine of the vital force became central to natural healing in a manner most consistent with Walter Cannon’s concept of homeostasis: Yet, we must ever keep in mind that there is no disease to be cured; there are only sick people to be healed… The physician must support the inherent nature of the patient by whatever means…By supporting the inherent power—the vital force—we re-establish a harmonious functioning of the disordered parts or functions.

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It is not the physician that cures, but the indwelling vital force that heals. Since it is the vital force that heals, we must seek those methods and do for the patient those things which will best support the natural healing powers of the particular person; we must be careful to do nothing that would interfere with that healing force. If we are not to interfere with the workings of the vital force in its attempt to heal, then we must carry on our practice in conformity with … the laws of nature. The mere use of a naturopathic method or modality does not mean you are practicing Naturopathy in conformity with its principles and philosophy. If such methods are used as a suppressive treatment, the physician is practicing Allopathic and not Naturopathic medicine. As naturopathic physicians we must work … in accordance with natural law. (“Editorial” by A.R. Hedges, DC, ND,72 Journal of the ANA, May 1950) 

Credit to Budden and Carroll The leadership of W. A. Budden and Robert V. Carroll was critical to the professional growth of natural healing from the mid-1930s to the early 1950s. Their alliance had begun formally in late 1934.73 From 1935 forward, Budden was the trailblazer in natural healing education. Robert Carroll became a trailblazer in the professional organization of natural healers, and through a network of common associates, they each supported the work of the other. Budden accepted the basic sciences as a necessary part of a “nonmedical” physician’s education, although he continued to argue that professional examinations were best given to candidates by each profession’s licensing board. He actually, in time, came to view the Oregon examinations as quite fairly conducted, and his students gained a high passing rate as the curriculum focused on these subjects as part of the core education in both chiropractic and naturopathy.74 

Education He continued at all times to commit his WSC programs to provide a sound and thorough education to his students in both the School of Chiropractic and the School of Naturopathy. He worked tirelessly to improve the standards for all similar colleges and took the lead at every turn in increasing the coursework and prerequisites required.75 But it must be understood that Dr. Budden considered chiropractic and naturopathy as complementary, as part of a complete package, and his friends and allies were like-minded; they were “DC, NDs.” Emblematic of this view are two events that took place in the mid-1930s: WSC joined in the school alliance known as the “Affiliated Universities of Natural Healing,” and Dr. Budden recommitted Western States to a broad natural healing, drugless, progressive curriculum. The first of these, the affiliation, was the brainchild of Homer G. Beatty, DC, ND, the president of the University of the Natural Healing Arts (UNHA) in Denver, Colorado. The four schools that were advertised in 1935 as being “affiliated” were Western States and the UNHA, joined by the Metropolitan College of Chiropractic and Physiotherapy of Cleveland, Ohio, and the University of the Healing Arts of Hartford, Connecticut. These schools were affiliated in recognizing that the goal of “a regular standard, four years of nine months each, course in Chiropractic and allied subjects is warranted by our profession and offered by the … school members of this affiliation.”76

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The commitment to curriculum was significant, and WSC was a leader in this area, especially in naturopathy. Western States was, as of 1933, located at 538 S.E. Alder Street, Portland, and remained at this location until late 1939. The WSC Schedule of Classes and Hours, first printed in May 1933 and in use throughout the college’s stay at the S.E. Alder location, set out a curriculum for both the chiropractic and naturopathy programs of 4000 hours of total study over 4 school years, each consisting of 8 months of residential attendance. The school year was September through July of the following year.77 The programs had 2750 hours of common study, starting with the basic sciences, and then “upper-class” requirements of 1250 hours specific to each program. Both courses of study had coursework in physiotherapy, electrotherapy, and hydrotherapy, with the major differences between the programs being the chiropractic coursework in clinical neurology versus the naturopathy coursework in herbology and biochemistry. In actual practice, students enrolled in the chiropractic program and then added the naturopathy program as provided for in the schedule: “After receiving either the D.C. degree or the N.D. degree, the other degree may be secured by an additional 4 months’ work; both degrees cannot be awarded within the regular course.” The graduating class of July 1937 was typical, with seven DC graduates, four of whom also received the ND degree.78 And Dr. Budden was firm in his commitment to a broad natural healing education and a corresponding view of the DC and ND professions. In 1935 he wrote to the Chiropractic Journal to object to the idea that “coagulation of tonsils and dehydration of hemorrhoids” were construed as surgery and therefore not defensible as part of chiropractic. He said, “Western States College stands foursquare behind the members of the profession who are engaged in the practice of electrotherapy as a part of chiropractic.”79 As the Schedule of Classes and Hours noted, under Oregon law, chiropractic was “that system of adjusting with the hand or hands the articulation of the bony framework of the human body, and the employment and practice of physiotherapy, electrotherapy and hydrotherapy.” As Dr. Budden’s letter went on to say: “There is no reason to back down or retreat from the position we have already established.” And he did not, either in the classroom, in clinical practice, or in any public forum. And finally, he made friendships and alliances deeply within both the chiropractic and naturopathic professions of his day. His chiropractic contributions and their effects on the DC profession have been written about elsewhere, but his naturopathic contributions and their effects have not been written about, and so some attention to his efforts in naturopathic education and professionalism will be paid here. He is known as a great chiropractic educator, one of the classic “schoolmen,” but he is also remembered “as a great naturopath.”80 

A Profession When Benedict Lust criticized the alliance formed by Budden and Carroll in late 1934, he was well aware of the Oregon Ballot Campaign and how hard the DC, ND alliance had fought in that 1934 effort. To emphasize the “push” that was necessary in that fight, Budden had addressed the 1934 Oregon Naturopathic Association annual meeting in June on the fight ahead. And through A.R. Hedges, DC, ND, and others in the ND community (which may have included Washington’s Carroll) and to boost interest, the ONA had Lust come out from New York for the meeting.81 Carroll, by all accounts of the events of the next 15 years of activities within the naturopathic profession, was frustrated by Lust’s interference in the political situation in the Pacific NW. What Lust had said struck at the very philosophy of the WSC with its School of Chiropractic and School of Naturopathy. Over the next 15 years, Carroll did three

things: he wrested control of the ANA out of the hands of Lust, the “president for life,” he made it a much more professional organization, and he backed Dr. Budden and Western States at every turn in the process.82 At the 1935 ANA convention in San Diego, Carroll pushed through a new constitution and supporting bylaws modeled on those perfected by the AMA. The state associations would have House of Delegates members based on the membership size of each state. The Board of Directors and Officers would be elected annually, and the Board would conduct much of the business of the ANA, primarily through its Executive Committee. Lust was elected again as president, but the “president-for-life” status was effectively rescinded.83 From this point forward, there were more voices within the ANA. Gradually, Robert Carroll took control of the reins of the naturopathic profession. The final split from the personal grip of Benedict Lust occurred in 1942. The annual convention of the ANA was scheduled for June 1942 in Chicago. The news of this location for the annual meeting had been released at the 1941 annual convention in St. Louis and continually publicized since November of that year.84 By the spring of 1942, Lust came to realize that he was to be challenged for the presidency of the ANA by a group led by Carroll that was seeking a more committed professional development within naturopathy. This group was largely from states that had licensing laws of some kind in place for naturopaths.85 As these naturopaths met in Chicago and elected Frederick Dugdale of Portland, Maine, as their president, Lust and his close associates, Jesse Mercer Gehman of New Jersey and T.M. (Teresa) Schippell of Washington, D.C., hurriedly convened their own meeting in Atlantic City, New Jersey. This meeting of about 70 naturopaths from the eastern United States, almost entirely from unlicensed states, was declared the convention of “the real ANA.”86 Even though Lust would contest the validity of what he called the “pseudogroup” of “pseudo Naturopaths,” until he passed away in the late summer of 1945—and his eastern followers would continue this even longer—it is clear that Dr. Carroll and the Western group acted within the full authority of the constitution and bylaws of the association and were in the “right” in this dispute. In any event, as Schippell wrote at the time, the western “insurgents” led by Robert Carroll had been working to “attract many outstanding naturopaths to their ranks, (and bring) in many state organizations to their membership” and had many “well-known practitioners.”87 Carroll assumed the presidency of the western ANA at the July 1946 convention and held the office for 3 years, until July 1949. 

The Merging of Efforts Carroll was a friend of Western States as president of the ANA and afterward as the group’s past president. In many ways, Western States came to have a favored status among schools that were connected with the teaching of naturopathy where Dr. Carroll and the western ANA were concerned. As the western ANA grew in stature, it began to make three goals clear: to unify all naturopaths in one professional organization (which meant unity with the smaller eastern group left after the death of Benedict Lust in 1945), to advance the goal of a naturopathic profession based in licensed states, and to develop its own clear educational standards. Unity was supposed to take place at the strong and successful Salt Lake City convention in July 1948, during Carroll’s presidency. It did not. But professionalism was much advanced by the creation of a strong committee and organizational structure that Carroll ushered in and by the enlistment of quality professionals like Alton C. Johnson, DC, ND, of California—the author of Principles and Practice of Drugless Therapeutics—into the western ANA membership.

CHAPTER 4  And the ANA adopted Budden’s model of a 4-year, 36-month residence course of study as its educational standard, passing a resolution at its July 1949 convention in Houston, Texas, against recognizing any school that (1) offered any of its instruction by correspondence; (2) offered diplomas rather than a course of instruction; (3) offered to grant multiple degrees for the same course of instruction; (4) granted any advanced standing or transfer credit that was based on study at schools not recognized by the ANA, the American Osteopathic Association, or the National Chiropractic Association.88 This was done as some of the last business conducted under Carroll’s presidency. In December 1949, the Journal of the American Naturopathic Association first published its list of approved schools, listing three schools that would require basic science credits from an outside institution of higher education and Western States as the only school offering residency education in all 4 years of the required curriculum. Moreover, Carroll strengthened the connections between the Oregon DC, ND community and Western States with the western ANA. Carroll personally quelled unrest among some of the ND community and Western States in the postwar years. He visited a regular meeting of the Oregon Naturopathic Association in December 1947 while ANA president, together with his successor as president of the Washington State Naturopathic Association (Dr. Helena Winters of Kelso, Washington). He then made another visit to the ONA monthly meeting a year later in December 1948. As reported in Oregon Pioneer, unrest began in the fall of 1948 within the ND community around Western States that the school was becoming known more as a chiropractic school, or a school of “chiropractic and drugless physicians,” outside of the college. Carroll made the purpose of his 1948 visit as ANA president to express his support for Dr. Budden and Western States as Budden saw fit to operate the college.89 After leaving the presidency in July 1949, Carroll remained active— somewhat more behind the scenes—in matters of the ANA and the Pacific Northwest. The largest issue for the Western ANA for 1950 was the unfinished business of unification with the remaining naturopaths in the eastern group, and for the year between the annual conventions of 1949 and 1950, this was almost all-consuming. Additionally, legal issues arose in Washington State in 1950 regarding the 1919 Drugless Healing Act under which the naturopaths in that state were licensed. These legal issues threatened to do severe damage to the profession’s legal status.90 Unification under the Western group’s national structure was achieved in St. Louis in 1950, although the amalgamation remained messy until the very end. Then, Dr. Robert V. Carroll, a true giant within the naturopathic profession and a friend of Western States College until the end, passed away suddenly in April 1951.91 

Firming Up the Curriculum—Chiropractic and Naturopathy From the time that Dr. Budden opened the “new” or “converted” Western States College in 1934, the curricula in both the School of Chiropractic and the School of Naturopathy showed his imprint.92 The primary philosophy-of-practice texts were Joy Loban’s Technic and Practice of Chiropractic, a text authored in 1915 by a leading faculty member from the National College program, and in naturopathy, Otto Juettner’s A Treatise on Medical Practice (the Art and Science of Non-Medical Therapeutic Methods), a text by a leading Eclectic and physio-medical practitioner. Juettner’s work was first published in 1916 and republished by Benedict Lust’s New York publishing house.93

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The other practice texts in use for the 1930s were Goldthwaite’s Body Mechanics and Marlin’s Manipulative Treatment for nonspinal adjustive technique, Grieve’s Modern Herbal for knowledge of herbal remedies, Luke’s Manual of Natural Therapy for hydrotherapy, Kovac’s Electrotherapy and Light Therapy for electrotherapy, Sherman’s Chemistry of Food and Nutrition for dietetics, and Boyd’s Preventive Medicine for hygiene and public health. The eclectic nature of these texts shows Budden’s wide knowledge of the subject areas included in the Western States curricula, but the use of Loban and Juettner’s works also reflects the fact that although the professions had grown significantly since WWI, the available scholarship had not. This began to change at the end of the 1930s with the publication in 1939 of Homer G. Beatty’s (of the University of the Natural Healing Arts in Denver) Anatomical Adjustive Technique and Alton Johnson’s first edition of The Principles and Practice of Drugless Therapeutics. Also published in 1939 by the National College of Chiropractic was Chiropractic Principles and Technic by Biron, Wells, and Houser of the NCC faculty; this was the first real advancement of the work begun at NCC by Joy Loban in the much earlier days of the profession. And in the late 1930s, John Robinson Verner’s The Logic and Science of Chiropractic first appeared. However, the onset of WWII not only slowed the progress of the colleges, but also the rationing of all materials, including paper, made the widespread use of these new works of scholarship problematic. For 1940 to 1941, the 1938 to 1939 WSC catalog simply had the additional date “1940 & 1941” stamped on the cover; no new catalog appears to have been printed until 1944, and no changes were made to the curricula for the duration of wartime.94 The 1944 catalog, which was used through 1947, included as new texts added to the curricula those by Beatty (added in anatomical adjustment); Biron, Wells, and Houser (added in palpation); and Johnson (1st edition; added in electrotherapy).95 Also, Rational Bacteriology by chiropractic scholars Verner and Weiant was added to the more standard text by Zimmer in bacteriology. 

New Developments in Postwar Scholarship It was not until the fall term of 1947 that new scholarship began to appear in use at an accelerated pace at Western States. The Logic and Science of Chiropractic by Verner (3rd edition, 1946) was added to the curriculum in chiropractic; in naturopathy, Thomas Lake, DC, ND’s Treatment by Neuropathy and the Encyclopedia of Physical and Manual Therapeutics was added. This latter work was a lengthy treatise published in 1946 on what was more generally known as mechanotherapy by a chiropractor-naturopath of some substantial reputation based in southeastern Washington State.96

Dr. Budden on Chiropractic and Naturopathy The first postwar catalog published was entitled “Bulletin of the Western States College, Announcement of the School of Chiropractic and School of Naturopathy.” The college symbol was now a hand holding a torch with the peroration fiat lux, or “let there be light.” For this first postwar catalog, Dr. Budden penned his own descriptions of chiropractic and naturopathy, both as to Pacific NW history and as to philosophy. This material became a constant in WSC’s postwar catalogs into the mid-1950s.97 Prospective students and interested parties were given this introduction to the WSC School of Chiropractic: School of Chiropractic, Founded 1908. The history of Chiropractic is largely the history of its schools. This is particularly true in the Northwest, where the energy and vision of the founder brought forth the D.D. Palmer School of Chiropractic in Portland, Oregon.

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As early as 1908 Dr. Palmer, together with Dr. LaValley, opened the doors of this pioneer institution. Since that day Portland has been the seat of Chiropractic learning in the Northwest. Always an institute devoted to this purpose has stood in the Rose City. The Western States College is therefore the lineal descendant and beneficiary of all that has gone before. It is carrying on the work of the founder as he would have desired it, in this modern manner. Chiropractic literature also found its birthplace in Oregon. The original text, “The Chiropractic Adjuster,” by D.D. Palmer, was published in Portland.” This was the introduction to the School of Naturopathy: School of Naturopathy, Founded 1930 The Latins spoke of it as the Vis Medicatrix Naturae—a remedial force or impulse. The Germans called it Natur Heiling, the remedial impulse of Nature, the self-recuperative power of the bodily system, independent of medicine. It has been described, also, as the capability of living tissue, animal or vegetable, to remedy and remove disease, or to repair the healing power of nature. United in man with the dynamics of the mind, this matchless force constitutes the basis of naturopathic therapy. To intelligently enlist it in the fight against disease is the whole art of non-medical healing. These two short pieces, authored by Dr. Budden, contain his synopses of chiropractic and naturopathy and present the central core of his nonmedical philosophy. 

More Curriculum and Postwar Scholarship By the fall term of 1949, as the Western States Class of 1953 was entering school, the full flowering of postwar scholarship in both chiropractic and naturopathy was available, and Dr. Budden took advantage of the newest works in crafting his curriculum for each program. Through the course of the college terms from fall 1949 to spring 1953 when the class of 1953 was in attendance at WSC, the chiropractic and naturopathy students were educated in two additional new works of nonmedical scholarship: Janse et al., Chiropractic Principles and Technic, 2nd edition, and H. Riley Spitler’s newly published Basic Naturopathy. This latter text was commissioned and published by Carroll’s western ANA with the intention of providing a definitive text in naturopathy. The scholarship is thorough and sound, and it holds up well today as “cutting-edge” work in its time.98 Budden paired Spitler’s text with a classic from the Eclectic–physio-medical school of medical philosophy, Clymer’s Nature’s Healing Agents: The Medicines of Nature (2nd edition, 1926) based on an adaptation of the Thomsonian System. This combination of Verner, Janse, Spitler, and Clymer plus the coursework in dietetics, physical fitness, body mechanics, electrotherapy, physiotherapy, and hydrotherapy demonstrated the clear imprint of Schulze and Lindlahr on Budden’s conception of the nonmedical physician.99 It cannot be overstated that Budden’s students were the broadscope chiropractors and naturopaths of the postwar era. The WSC students Budden produced kept these professions alive, especially in the Northwest, for the next 30 years, into the mid-1970s. This postwar era was the zenith of the period when WSC was the pacesetting educational and scholarship beacon in chiropractic and naturopathy. This postwar period was the WSC era when WSC was the intellectual environment that would be rivaled in the middle age of the professions perhaps only at National College.100 

A.R. Hedges, DC, ND, and W. Martin Bleything, DC, ND— First Connections Another of the friends and allies Dr. Budden first grew close to professionally during the 1930s was A.R. Hedges, DC, ND, of Medford, Oregon. Medford is a smaller city about 275 miles due south of Portland, located just north of the Oregon–California state line. In 1930 when Portland’s population was just over 30,000, Medford’s population was just over 11,000, and the “greater Medford” population (within a 5-mile radius of the city center) was just under 17,000.101 A.R. Hedges had been practicing as a drugless physician in Medford since 1911. His advertisements for his practice with his wife Louisa for their “chiropractic-naturopathic” offices had appeared in the Medford Mail-Tribune as early as 1913.102 Both A.R. and Louisa appeared in Benedict Lust’s Universal Encyclopedia Directory and Buyer’s Guide— Year Book of Drugless Therapy for 1918–1919 as active drugless healers in Oregon. Whether by coincidence or not, Dr. Hedges did not appear on the statewide Oregon scene as a leader in either chiropractic or naturopathy until 1929, just as Dr. Budden was arriving on the scene as well. From here on, the professional arc of these two DC, NDs intersected continually. At the June 1929 annual meeting of the Oregon Chiropractic Association (OCA), the forerunner of the OACP, Hedges was named by the OCA president to the convention’s resolutions committee. This is the first time he appears in any news coverage of OCA affairs. It was at this conference that Dr. Budden gave his first of many addresses to the Oregon profession. Although it is not clear that the two first met each other at this meeting, Dr. Budden drove down to Medford in March 1930 for a Saturday evening meeting of the Southern Oregon Branch of the OCA held at Dr. Hedges’s home in Medford. The Southern Oregon Branch was the professional business section for the southwestern region of the state between annual meetings of the OCA.103 Budden was in the company of the OCA’s president and the secretary of the state Board of Examiners, both doctors from Portland. Plans were being made for the next annual meeting, which was to be held in Medford for the first time. The upcoming legislative session and legislative planning were also discussed.104 Dr. Budden would attend meetings of the Southern Oregon Branch many more times over the years. By the next summer, Hedges was named to his first 3-year term on the Oregon Board of Naturopathic Examiners, serving from 1930 to 1933. Over the course of the 1930s, Dr. Budden and Dr. Hedges crossed paths many times during the professional activities of both the OCA/OACP (the progressive “mixer” group of the state) and the naturopaths of Oregon. This was particularly true during the 1934 Ballot Campaign, in which Dr. Hedges actively participated.105 It would be during the war and postwar years that the association of Drs. Budden, Carroll, and Hedges would have its greatest import for Western States College. But before moving the story forward into the war years, it is necessary to introduce W. Martin Bleything.

Dr. Wallace Martin Bleything Dr. Wallace Martin Bleything first appeared on the Oregon scene in 1937 when he was on the speaker’s roster for the 1937 annual meeting of the Oregon Association of Chiropractic Physicians, the successor to the Oregon Chiropractic Association. This was a meeting held at WSC that also featured Dr. Carroll as a speaker, and the 1937 WSC commencement was held in conjunction with this event.

CHAPTER 4  The subject of Bleything’s speech on this occasion is not known from the news clip available, but at the time, Bleything was working for a research laboratory in Los Angeles. In 1941, just before the United States entered WWII, Bleything appeared as a speaker before an osteopathic postgraduate meeting in Amarillo, Texas, giving a series of talks on endocrinology, a subject for which he was listed as a “nationally-known expert.”106 Just after war broke out, he was awarded his Master of Chiropractic degree from the California Chiropractic College of Oakland, California.107 

Hedges and Bleything—the War and After As America went to war, Hedges’s professional profile continued to rise as a physician who had been in practice for 30 years. In July 1942 he was elected vice president of the Oregon Association of Chiropractic Physicians, and in December of that year he was named once again to the Oregon Board of Naturopathic Examiners to finish a term (through July 1, 1943) for a member of the Board who had passed away.108 In July 1944 he was elected the OACP president at the annual meeting, and he served as president until July 1946. The vice president elected with him in 1944 was another DC, ND, J. W. Sargent, who had worked with Hedges and Budden going back to the 1934 Ballot Campaign if not longer.109 In fact, there was clearly considerable overlap in the 1930s and 1940s between the OACP and the Oregon Naturopathic Association. In 1946 as his successor as OACP president was being elected, Hedges was reappointed to a full 3-year term on the Oregon Board of Naturopathic Examiners.110 In 1949 at the July convention of the ANA in Houston, Hedges was elected second vice president (VP), taking office as Carroll stepped down as president. By November 1949, his hometown Medford newspaper was reporting on his travels across the country in his national position.111 Hedges was now positioned to protect the interests of WSC with the national ANA as well as Carroll, and he continued to do so. Hedges served as second VP of the western ANA for 1 year until July 1950; then, as part of the newly unified ANA, he was elected first VP and twice reelected, serving as first VP from 1950 to 1953. At the 1951 annual meeting, the association had gone through a name change to the American Naturopathic Physicians and Surgeons Association. Hedges wrote the editorial in what was now the Journal of the ANPSA explaining the long story behind the earlier schism, unification, and the reason for the name change.112 He also wrote a series of editorials in the association journal eloquently explaining the difference in core philosophy between the allopaths on one hand and naturopaths and chiropractors on the other; the difference between viewing the physical organism as operating in “conformity with the laws of chemistry” versus the view that the body “is in a vital realm, presided over by a vital force” that maintains life; and the difference between treating symptoms with suppressive means versus “supporting the vital force” to “regain harmonious function” and “to do nothing that would interfere with that healing force.”113 In July 1953 he was elected president, and he was reelected July 1954, serving until mid-1955. This was all capped off for Dr. Hedges when he appeared before the Oregon Naturopathic Association annual meeting in March 1954 as national president.114 Throughout these years, Hedges succeeded Carroll in guarding the interests of the Western States program at both the state and national levels. In 1947 the Los Angeles College of Chiropractic dropped its ND degree program. In 1949 the Metropolitan College of Chiropractic closed. Then in 1950, Homer Beatty of Denver’s University of the Natural Healing Arts suddenly passed away, and the National College of Chiropractic

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dropped its ND degree program. Through these events, the other legitimate, 4-year residency programs were lost. As the largest and strongest organization of naturopaths, the ANPSA had a vested interest in the existence and success of WSC. That brings matters back to Dr. Budden and WSC as the war ended in 1945. Dr. Wallace Martin Bleything, known most often as W. Martin Bleything or Martin Bleything, appears to have been linked primarily to Western States in the postwar era. As the war came to a close, Western States was hanging together but uneasily, as already described. With peace came the wave of returning veterans and a postwar boom of interest fueled by the Servicemen’s Readjustment Act of 1944, or the “G.I. Bill.” About 2.2 million returning veterans used their G.I. Bill benefits to attend colleges or universities, the classification attained by Western States through the Veteran’s Administration, which certified institutions of higher education.115 As Lester Lamm described the circumstances of Western States in Oregon Pioneer: The shortage of students produced by the Great Depression and made worse by World War II disappeared almost overnight, leaving the college with a completely new challenge: what to do with more applicants than the institution could manage. The G.I. Bill filled college and university classrooms across the nation, and the Western States College was the fortunate beneficiary of escalating applications and enrollment numbers. The explosion of growth was unanticipated and the college was not prepared for the magnitude of the student influx it experienced. The makeup of the student population was also challenging. Students demanded the administration provide them with a higher quality education, in a more appropriate facility.116 The school resolved the facilities space problem in late 1946 by purchasing a building on S. E. Alder in Portland, a former lodge building. As A.E. Homewood described it, “this was far from ideal, or a place of beauty, but did offer the necessary space for expansion.”117 Qualified faculty was another matter. The size of the new student population surpassed the method of Dr. Budden doing a lot of instruction supplemented by local practitioners. Enter, among others, Dr. Bleything. Bleything had a varied and colorful background, but most relevant to Western States, he had grown up in Portland, then moved to Seattle shortly before World War I. Interrupted by service during the first war, he had studied chemistry and then worked and studied at Grace University Hospital, a homeopathic and drugless physician training program combined with a sanitarium maternity ward run largely by a homeopathic, fully licensed MD. John Bastyr, DC, ND, after whom Bastyr University is named, had interned there, and Dr. Robert Carroll had been on the sanitarium staff, both during the 1930s. Between 1932 and 1942, Bleything had worked at a research laboratory in Los Angeles as a colloidal chemist, as well as graduating from chiropractic college.118 Bleything arrived at WSC in 1947 and joined the faculty in firstand second-year basic sciences and in third- and fourth-year practice courses in chiropractic. He got licensed in Oregon as a DC and became a member of the OACP. Within another year, he got licensed as an ND and joined the ONA. By 1951 he had been recruited by A.R. Hedges to take over as editor of the Journal of the American Naturopathic Association and had become the lead faculty member in instruction in the naturopathy program at Western States (while still continuing with the basic sciences). Again, Western States had connections deep into the national affairs of naturopathy and was the example naturopaths always turned to when the education of NDs was challenged.119 

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The Western State College Class of 1953

Universal health care—a totally government-funded healthcare system—was a pronounced political goal of President Harry Truman. The political and public relations machinery of the AMA was almost entirely directed at this “threat” to the “American Way” for all of President Truman’s postwar term in office. While organized medicine was politically preoccupied, chiropractic and naturopathy were able to advance. President Truman left office in January 1953, and by the summer of 1953, the AMA was starting a national campaign to eliminate chiropractors and naturopaths as competitors, but until then, battles were fought on a state-by-state basis.121 As previously discussed, the National Chiropractic Association (NCA)—the chiropractic “mixer” group—was directing its accredited colleges to shut down any of their nonchiropractic degree programs, specifically any ND degree programs. After National Chiropractic College complied in 1950, Dr. Budden was the lone holdout in maintaining a naturopathy program. The push in this direction was led by John Nugent, the “Flexner of Chiropractic.” In meetings of the education council of the NCA, Dr. Budden was merely resistant; behind closed doors, Dr. Budden and Dr. Nugent had loud, if personally respectful, disagreements about this subject. Dr. Budden was unyielding.122 And so the postwar period of 1946 to 1952 was a period of professional development in natural healing and of advances in clinical science and in serious scholarship. But in DC, ND education, Western States was alone after 1950. This was, at the same time, WSC’s most fruitful period under Dr. Budden fueled by the G.I. Bill—the only public funding program for DC and ND education until the rise in the 1980s of student loan and Pell Grant funding. 

hours of instruction, and summer term was 100 hours, for a total of 1000 hours the first year. This increased to 1160 for the second year, 1260 for the third year, followed by a fall and winter term fourth year of 940 hours. Degree completion for either the chiropractic or naturopathic degree came at the end of the spring quarter the fourth year.123 The first 2 years were intense with the basic sciences curriculum (as such programs are today) together with either Introduction to Chiropractic or to Introduction to Naturopathy, followed by Principles of either discipline included in the first 2 years. The students largely lived and breathed this coursework for 4 years, with most of the social activities that the students had being activities like clubs and dances at the college. This class of 1953 was mostly veterans, a bit older, a bit more ready to get to work and on with life, and mostly married. And they were from throughout the country and from British Columbia, Canada. There were eight each from Oregon and Washington; three from California; two each from Missouri, North Dakota, Minnesota, and British Columbia; and one each from Nebraska, Illinois, Michigan, Colorado, Montana, and Ohio. There were five women in the class and two African Americans, one of whom, being from Miami, had come the farthest from home to study at Western States. Emblematic of the initiative of this class of 1953, class members started a monthly news publication entitled The Synergist: Western States College Voice of the Student Body, “published in the interest of UNITY among all interested drugless healing arts.”124 This monthly publication is virtually a journal of this class of 1953, disappearing as a monthly when the class of 1953 graduated and surviving as a bimonthly only for another year or so. But while this class was enrolled at WSC, it was their voice. Another aspect of the quality of WSC and its student body, and the class of 1953, particularly, was its racial integration. Two members of this class that entered in the fall of 1949 were male African American students who graduated with the class of 1953. One of these students came completely across the country, from Miami, Florida. Jackie Robinson “broke the color barrier” in baseball in 1947. President Truman desegregated the American Armed Forces by Executive Order in 1948. The Warren Court did not strike down the segregation concept in public education until 1954. The enrollment of these two students and their integration into the graduating class of 1953 speaks volumes about the progressiveness of Dr. Budden, of WSC, of the students of the class of 1953, and of the city of Portland in general. The members of the class participated in two designated “fraternities,” Sigma Phi Kappa, a chiropractic fraternity founded in 1912 and chartered at Western States in 1948, and Phi Nu Sigma, a naturopathic fraternity started at Western States modeled on Sigma Phi Kappa. Phi Nu Signa announced in The Synergist for February 1953 that it was starting the process of “expanding its sphere of influence by providing for and inviting practicing Naturopathic Doctors to join its ranks to help promote Naturopathy and naturopathic principle and practice.” This last item seemed to be a parting gift from the leaders of the class of 1953 to the fraternity and also a way to stay involved themselves as new NDs.

Enter the Class of 1953

As Reported in The Synergist

By the fall quarter of 1949, the college had settled into a former lodge building at 4535 S. E. 63rd Street. The curriculum was set as well, and the students were expected to attend straight through for three quarters plus summer term in each of the first 3 years of attendance, and two quarters in the fourth year. The schedule started the first week of October and went through the end of July of the following year; the fall, winter, and spring quarters were each 3 months long, and summer term was the month of July. Each regular term was 300 classroom

The initiative of the class of 1953 becomes clear in looking at its own documentation of itself and of the larger WSC student body in The Synergist. By the time of the class of 1953 commencement ceremonies in March and July of 1953, The Synergist was publishing regular news submitted for publication by both the OACP and the ONA. This provided the student body with a regular source of professional news, and The Synergist became a publication subscribed to by the professions as well.

By 1946 the way was now clear for the Western States programs and the chiropractic and naturopathic professions to establish themselves in peacetime. In the fall quarter of 1949, the Western States class of 1953 entered the college. By the time the class of 1953 graduated, the majority had finished with both DC and ND degrees, and the graduating class of the School of Naturopathy was the largest class of ND degree holders ever at WSC. It was also the largest such class anywhere for another 30 years—until the John Bastyr College of Naturopathic Medicine in Seattle graduated its first full class in 1982. The class of 1953 would make its mark in keeping alive both broad-scope chiropractic in Oregon and elsewhere and naturopathy in Oregon, Washington, and the Canadian province of British Columbia for that same 30-year period. In the immediate postwar period, 1946 to 1952, the AMA—or organized medicine—was consolidating its power within the US healthcare system. Medical dominance was present, but as a threat to alternative practitioners, it was not yet at full throttle. This was, looking back historically, because of the AMA’s obsession with the threat that organized medicine called “socialized medicine”—a healthcare system controlled by the federal government.120 

The AMA and President Truman

CHAPTER 4  In the postwar era, Western States became a fixture of natural healing under Dr. Budden. The Synergist captured this in documenting the professional activities and meetings that took place at the college and the participation of Dr. Budden, the faculty, and student body in these events. As an example, The Synergist for May 1952 recapped the annual OANP meeting that had been held at WSC in March 1952, at which the featured keynote speaker had been Henry J. Schlichting Jr., ND, national president of the ANPSA.125 The same edition of The Synergist reported the complete program for the annual meeting of the Oregon Association of Chiropractic Physicians to be held at WSC the first week of June that year. Dr. Schlichting, it was reported, had given an open speech to WSC students and staff, to physicians, and to the public, as well as a speech to the convention banquet. The Synergist reported in the column “Naturo-News” authored by Dr. R.A. Rombaugh of Independence, Oregon, that Dr. Schlichting “lauded the pioneers and early educators and complimented Dr. W.A. Budden, Western States College Director on the fine job in building the College to today’s high level of standards.” The schools Dr. Schlichting said, were “the life blood of any profession.” Another initiative of the class of 1953 was an annual WSC picnic. The first reported “WSC Annual Picnic” was to be held Sunday, June 15, 1952, but was postponed a week due to inclement weather. But when it was held on June 22, 1952, as reported in The Synergist for July 1952, it left all attendees and participants “looking forward to the picnic next year.” More impressively, the picnic was attended by both members of the Oregon Association of Naturopathic Physicians and the Washington Association of Naturopathic Physicians, as reported in the Journal of the American Naturopathic Physicians and Surgeons Association (vol. 5, no. 2, June 1952). 

More Professional Matters for Dr. Budden Three other events of interest occurred during 1953 that affected the class and were noted in The Synergist. First, the Oregon chiropractic scope of practice came under assault again, from the medical profession on one side and the “straight” chiropractic group on the other. A breakfast meeting of the Oregon Joint Legislative Council held Saturday, March 7, 1953, was broadcast on radio and moderated by radio commentator (and future Oregon governor) Tom McCall. The specific subject was pending Senate Bill 134, yet another bill to strip obstetrics and minor surgery from the Oregon chiropractic scope of practice.126 Dr. Budden appeared with another physician from the OACP representing the Joint Legislative Committee of chiropractors and naturopaths. The medical view was provided by representatives of the Multnomah County Medical Association, both of them clinical professors at the University of Oregon Medical School, one in OB/GYN and one in general surgery. When asked by McCall about the fact that Palmer College did not teach these subjects as “The Fountainhead” of chiropractic, Budden related some of the history of “straights” and “mixers” and told the audience that one major issue was that the Palmer school did not wish to go to the expense of teaching these subjects even though it had adopted a 4-year curriculum in 1953. By the following Tuesday, the Oregon Chiropractic Research Association—the Oregon “straight” organization, a group in Oregon about one-fourth the size of the OACP—had issued a strongly worded communique to the radio station that broadcast the discussion and to The Oregonian newspaper. The statement said that the OCRA had nothing to do with the pending legislation and no interest in it, but it took offense at Budden’s characterization, noting that Palmer devoted 4485 class hours to “straight” adjustment technique and that Budden “attempted” to teach a laundry

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list: spinal adjustment, obstetrics, surgery, eye-ear-nose-throat practice, proctology, proctology, removal of tonsils (by electrotherapy), administering anesthetics, use of hypodermics, electrotherapy, hydrotherapy, physiotherapy, “and such” in 4240 class hours.127 In the long run, once again, no legislation was passed, altering the Oregon scope of practice.

Some Positive Developments What did pass at the insistence of Dr. Budden and Western States College, and with the support of both professions, was House Bill 271 (NDs) and 272 (DCs) increasing the educational requirements to high school plus 2 years of college credit from an accredited college or university. This was noted in an approving editorial in The Synergist for February 1953, penned by Appa Anderson. Finally, it was noted in The Synergist for March 1953 that as president, Dr. A.R. Hedges was bringing the American Naturopathic Physicians and Surgeons Association convention to Portland that summer, in July. The general chairman for the convention was WSC’s Professor W. Martin Bleything.128 

1953 for the Class of ‘53 The April 1953 issue of The Synergist contained a column by the editor of the O.A.C.P. Journal; this column had by now become a regular presence in The Synergist. The editor was A.C. Johnson, WSC class of 1951. He paid a special tribute to the class of 1953, saying “without reservation, I would like to praise a universally qualified and most ambitious group.” He paid special tribute to those “from this group, (that) have become the working force that has published The Synergist during these past four years,” and closed with: “To the class of '53, and with gratitude to you who have done so much to keep the college, the students, and the profession interested and united, we, the profession, wish you God speed in the gratifying endeavor that awaits you.” And then this remarkable class prepared to graduate and pass into the history of Western States. For some comparison, in June 1949, WSC graduated 36 DC degrees and 16 ND degrees, with 11 graduating with dual degrees. In March 1950, WSC graduated 29 DC degrees and 2 ND degrees. In March 1951, 21 DCs graduated and 4 ND degrees. In March 1952, 31 DCs and 1 ND graduated. The class was scheduled to graduate in March 1953, and most were graduating as DCs. Because there was interest expressed among class members in receiving dual degrees, a special spring quarter schedule had been arranged, focused exclusively on ND therapeutics. The Synergist had reported this development from time to time over the 1952–1953 school year. It was noted in the March 1953 publication: “much of the class will be around after Graduation to take a post-graduate course in Naturopathy, so we really won’t be saying our goodbyes for a while” This course for DCs required a full spring quarter of coursework in Cyriax’s Text-book of Orthopaedic Medicine, Volume II on massage therapy, Mausert’s Herbs for Health, and Spitler’s Basic Naturopathy in a course designed by Drs. Budden and Bleything. The class of 1953 had two commencement ceremonies, one in March and one in late June. In March, 33 DCs and 2 NDs graduated, with 7 DCs also receiving the BTS degree and 1 ND receiving the BTS degree. In July, at a special commencement at the end of the spring quarter, 33 NDs were graduated, and 1 received the BTS degree. Twenty-six of these degrees went to DC graduates from March 1953, three went to March 1952 DC graduates who returned for the spring quarter course, and six ND degrees were received by ND candidates who finished studies in June with the extra quarter’s work. The late-June ND degree ceremony was staged as an evening event on the second night of the ANPSA convention, as reported in the Journal of the ANPSA for September 1952 (vol. 6, no. 6). “The

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commencement address was delivered by that outstanding authority on nutrition of the University of Missouri, William Albert Albrecht, Ph.D. Dr. Albrecht’s address was indeed inspiring, not only to the graduates but to all in attendance.” And, as the reporter noted: “It was indeed an inspiration to see this fine young group of naturopathic physicians entering the profession. The profession needs more young naturopathic physicians to assure its future.”129 

Some Stalwarts of 1953 Joseph Boucher, the ND degree graduate who had been student body president for 1952 to 1953, received the William J. Gallagher award as the outstanding graduate of the class of 1953, with Appa Anderson being noted by Dr. Budden in announcing the award as a close second. And then the class of 1953 left Western States to conquer the world. But this class was the fruition of all that Dr. Budden and the chiropractic and naturopathic professions had built at Western States in the face of challenges and opposition. Dr. Budden died unexpectedly in August 1954, less than a week after returning from attending his last NCA meeting.130 By the time the class of 1953 finished its first year at Western States, the ND program was the only remaining ND program in the United States.131 Within 2 years of the death of Dr. Budden, the ND program at Western States was discontinued; courts had restricted the legal scope of practice in Washington and Arizona; and licensing of NDs was lost completely in Texas due to actions by the courts and in South Carolina, Utah, and Florida by legislative action. How this happened is another piece of history still to be told, but a great deal of it curbed broad-scope or “mixer” practices in those states, and a large factor was medical dominance, what the educators and physicians discussed here had battled for 25 years. Things did not improve until at least the 1980s, another part of the story yet to be told. But that should in no way diminish what was done at Western States College and in both its School of Chiropractic and its School of Naturopathy. From the class of 1953, Joseph A. “Joe” Boucher, ND, BTS, became a giant of Canadian naturopathy in his own right,132 Appa Anderson stayed at Western States for an impressive career of her own in chiropractic radiology,133 and Professor W. Martin Bleything was one of the founders of today’s National University of Natural Medicine, together with one of his fellow faculty members and a former Western States student from the class of 1952.134 Ralph M. Failor, who—along with his wife Hazel—received a DC degree in March and an ND degree in July, would succeed Dr. Budden as president of WSC. He would in time become a big part of the history of WSC.135 What happened was remarkable and needs to be better known. 

PART TWO: WHAT HAPPENED TO THEM? Moving On There may be no more exemplary story in the development of natural healing among chiropractor-naturopaths than the story of Henry J. Schlichting Jr., of Midland, Texas. Schlichting was trained as a chiropractor in Oklahoma and moved to Texas in 1941, setting himself up as a naturopath. At the time, neither chiropractors nor naturopaths were licensed in Texas. Schlichting became a leader within natural healing professionals, first within Texas and then nationally. He became a trusted ally of both Robert Carroll and of Dr. Budden at Western States College. He and his Texas naturopaths achieved licensed status in 1949. In the early 1950s, all looked bright, and then it all turned dark. On the evening of July 17, 1953, the commencement for 37 recipients of the degree of doctor of naturopathy took place in the auditorium at Western States College in Portland, Oregon. This special commencement was scheduled as the Tuesday night program for the

1953 annual convention of the American Naturopathic Physicians and Surgeons Association, as the immediate past president of the ANPSA Henry J. Schlichting Jr. of Midland, Texas, was in attendance.136 As Schlichting had said a year earlier in a speech at WSC, the prospects for naturopaths seemed good as this WSC class of 1953 graduated, most of them as DC, NDs. But the forces of medical dominance were building, starting back home in Texas, even as Schlichting was attending the convention in Portland. Within 6 years, natural healing in the United States would be much diminished. No career demonstrates this as clearly as that of Schlichting, a remarkable man and physician who, by the end of the 1950s, had been barred by the State of Texas from practicing his chosen profession and who had lost almost everything. When the class of 1953 graduated from Western States, the leadership of the naturopathic part of the natural healing professions was in Henry Schlichting’s hands as the president of the ANA, with A.R. Hedges in line to become Schlichting’s successor. There were headwinds, though, just beginning to be felt. 

HEADWINDS Some of these headwinds had been building within the naturopathic movement itself since the 1930s. Benedict Lust criticized Dr. Budden and Dr. Carroll in early 1935 for proposing a continuing alliance based in the Pacific NW between broad-scope chiropractors and naturopaths. The 1935 annual ANA convention a few months later in San Diego was a crossroads event for ND as a profession. Lust opened the convention with a presidential address that seemed to mark a “scofflaw” phase in Lust’s career as the head of the naturopathic movement. He told the convention that he had been prosecuted—and persecuted—for issuing diplomas to “doctors” from the American School of Naturopathy without a New York State charter to do so. The State of New York, he charged, was operating as an arm of the AMA’s “Medical Trust.” Only naturopaths, he told the convention, could decide who deserved to be called naturopaths, not the state or the Medical Trust. Naturopathy needed to be accepted by the public to be legitimate, not by the state. But for the first time, Robert Carroll brought a countervailing view to an ANA convention. These countervailing visions of the future of naturopathy were the visions that played themselves out over the next 10 years within the ANA. The ANA could not be a movement run by a permanent leadership but needed to truly be a professional organization seeking to advance a natural healing profession. In adopting a new constitution and bylaws proposed by Carroll, the ANA accepted Carroll’s vision of the future over Lust’s vision from the past. By 1937 Carroll was comfortable that the ANA was in a good place; now it was time for the profession to accept that fact. At the end of 1937, as the chairman of the Executive Committee of the ANA, Carroll issued “An Appeal to All Naturopaths.” He opened by saying that he for some time he had been “alarmed and rather disappointed with the seeming indifference of many of the Drugless Physicians to our National Association.” “Progressive Naturopaths,” he said, were committed to the goal, through the ANA, that “our profession will take its place as a scientific body of learned naturopaths.” With science on its side, progressive naturopaths could, for example, “tell the world just why Sulfanilamide is detrimental to the human body, and in just what kind of cases it is fatal or contraindicated—This must be our objective if we ever hope to merit the respect of the public and our educational institutions.” Changes had been made in the ANA in 1935 “to pull our profession out of the adolescent state, which we have seemingly been unable to pass.” As part of the change in ANA structure, the leadership of the ANA also gained some input into submission of ANA professional material in Naturopath and Herald of Health in exchange for ANA dues monies

CHAPTER 4  being used to support Lust’s costs of publication. Using this position, Carroll had an article by Dr. Budden on the effects of the Basic Science Laws published in NHH. The article also appeared in one of the leading chiropractic journals. 

Revisiting Basic Science This article was written in Budden’s inimitable style and was written only a couple of years away from the Oregon 1934 ballot fight that marked Budden’s initial response to Oregon adopting its Basic Science Law. In a classic Americanism argument, Budden pointed out that a “whole generation of college-bred men and women” would be good national policy as there “should be more and evermore of our youth attending institutes of higher learning, and provisions should be made to make this possible.” But there were policies that were intended to work against “Americans who value democracy” and that had the “sinister objective, nothing less than the establishment of exclusive privileges in education.” This was where, Budden argued, the Basic Sciences Laws were directed. They were designed as a test of university-level sciences divorced from the application of the sciences to drugless, nonmedical professions. This was at a time when “the drugless world had developed its own schools and colleges; institutions of learning peculiar to human therapeutics from the non-medical standpoint, well-equipped and staffed by competent teachers.” “Drugless schools,” he pointed out, “have no state support and few endowments; they must depend on contributions from alumni and upon tuition.” And as “a great national magazine (had) brought to light the unpleasant truth [was] that more people gave allegiance to physiological and drugless methods than to purely medical treatments.” If “the drugless schools continued to flourish and to increase in value to the community and the country at large, it soon be too late to attack them. Thus the basic science idea was born.” Budden went on to argue that “it is important to note that in most states, and in the state of Oregon in particular,” the sciences called the basic sciences—anatomy, chemistry, physiology, pathology and public health—were already taught and tested on for chiropractic and naturopathy. The purpose of the “extra” examination seemed to Budden to be an attempt to raise a barrier to drugless, nonmedical students of chiropractic and naturopathy with a clear ulterior and undemocratic motive: to keep these practitioners out of the marketplace: “Proponents of the law maintain that by this arrangement, which they contend is fair to all alike, the public is assured of a higher grade of practitioner. The police power of the state should be wielded to protect the public: not one particular group of physicians. The way of safety for the citizen is not in uniformity of thought in the healing arts, but in diversity.” Dr. Budden had come to be recognized by Robert Carroll as one of the leading “schoolmen” in natural healing. Although Budden was very concerned about “a board composed of university lecturers or Deans, men who know nothing of drugless practice and care less, prejudiced even before they occupy positions on the basic science board,” he came to believe within less than 10 years of dealing with the Oregon board that the examinations were fairly held—which will be addressed later in this chapter. A similar set of countervailing visions to those playing out within naturopathy played out within the National Chiropractic Association. In 1939 the influential broad-scope (or “liberal”) chiropractor from Montana, C. O. Watkins, DC, argued in an influential article137 that chiropractors should not favor separate licensing and degree status for naturopathy; rather, chiropractic statutes should be sought legislatively, recognizing that naturopathy was incorporated within a broad conception of “liberal” chiropractic and should be recognized as such.

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In the article, Watkins noted that nationwide, there were “16,000 chiropractors, 95 per cent using other than straight Chiropractic” and “2000 naturopaths, many of them holding Chiropractic licenses who could also be considered liberal chiropractors.” Furthermore, Watkins noted, the NCA had considered the issue of backing naturopathic legislation and decided on a different policy: “That the NCA oppose any plan that would cause the passage of separate physio-therapy laws or naturopathic laws to cover liberal chiropractors, but rather favor liberalization of Chiropractic legislation where it desirable to legalize liberal practice.” Looking back through the lens of historical hindsight, it seems that these policy differences fostered a diffusion of energies that would have been better spent seeking recognition for natural healing in the most expansive way possible, wherever possible. 

And Scandals Although most developments that have been discussed thus far were positive, in the 1940s, there were scandals involving practitioners identified as “naturopaths” as well. In 1938 a group of liberal chiropractors that identified themselves as chiropractor-naturopaths had formed the American Naturopathic Association of Michigan. Their leaders were charged with bribing members of the Michigan state legislature during the 1939 and 1941 legislative sessions. The charges alleged that bribes had been paid in an effort to get a naturopathic law enacted, and reports of the investigation by an inquiry judge, including the charges brought and the trials and guilty pleas in the case, dominated upper Midwest headlines from late 1944 through the end of 1945. A much bigger scandal—one that received much wider and more sensational coverage—emerged in Tennessee. By the time the events there had played out, the courts had laid the groundwork for the assault on naturopaths that took place 10 years later in the mid-1950s. Organized naturopathy came to Tennessee in December 1937 when the ANA of Tennessee was chartered. Guy W. Cheatham, DC, ND, had established the Nashville College of Chiropractic and Naturopathy earlier in the 1930s, and the school and the ANA of Tennessee operated in an unlicensed vacuum for several years while Cheatham was active in the NCA efforts on chiropractic education and in ANA national affairs. George A. Floden, DC, ND, of Los Angeles, California, was affiliated with Cheatham’s college and lectured there on a regular basis. Matters in Tennessee changed significantly and abruptly in 1943 when the Speaker of the Tennessee House of Representatives, backed by the Crump political machine based in Shelby County (Memphis), pushed through a naturopathic licensing law over the veto of the state’s governor. A 1946 investigation suggested that two naturopaths who later were named to the naturopathic licensing board funneled several thousand dollars to the Speaker (one bookkeeping entry showed $7835 for “1943 legislature”), their golfing buddy, in the form of “friendly” golfing bets. By 1946 the examining board, which by statute kept its own books and records of licenses issued, had issued 917 Tennessee licenses to “naturopaths” from as far away as California, Alaska, Mexico, Canada, and South Africa. The number could actually have been more than 1000 licenses issued, as the books and records of the examining board “disappeared” from the offices of one of the board’s members while the records were under subpoena by state prosecutors. But investigation showed that some diplomas and licenses were sold as a package: $1500 for a diploma and $1500 for a license. In December 1946, 27 indictments were issued by a grand jury in Nashville. Those charged included Guy Cheatham DC, ND, and his California associate George Floden, DC, ND, along with a California associate of Floden. Two Texas NDs who lectured at Cheatham’s Nashville College were charged as well, and in the grand jury’s 34-page

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indictment, it was alleged that all schools of naturopathy in Tennessee were “diploma mills.” Cheatham had, admittedly, issued “naturopathy” diplomas to earlier chiropractic graduates of his college so that they could apply for naturopathy licenses after the 1943 statute went into effect. In all, 17 defendants submitted nolo contendere (“no contest”) pleas and were fined between $100 and $1000. The largest fines of $1000 went to two of the three members of the licensing board that the prosecutor said were “to blame for the conspiracy.” Charges against Flodden and his California associate were dropped when the State of California denied extradition to Tennessee on the charges. More importantly in the long run, the 1947 Tennessee legislature repealed the naturopathy act, criminalized any future practice of naturopathy in Tennessee, and invalidated all existing licenses to practice naturopathy in that state as of January 1947. Ten practitioners—all members of the ANA of Tennessee and all “clean” of any taint from the indictments—filed suit, seeking a declaration by the courts that the repealer statute was constitutionally invalid because it deprived them of their valid property interest in their licenses to practice without due process and without any finding that naturopathy itself was a threat to the health and welfare of the citizens of Tennessee. A chancery court (trial-level) judge agreed, holding that the legislature did not have the constitutional authority to rescind the right to practice a legalized profession and to revoke, carte blanche, an entire class of professional licenses from practitioners who were without fault. A request to enjoin any enforcement of the statute through prosecutions for practicing medicine without a license was denied as beyond the authority of the court. But before 1947 was over, the Tennessee Supreme Court had reversed this judgment. The Supreme Court held that the allegations of massive fraud in issuing licenses were serious enough to justify a sweeping response under the state’s constitutional police powers, without the necessity to review each license in question. Moreover, the Tennessee court held that it was well within the police power of the state legislature, under the same constitutional police powers, to repeal an entire class of professional licenses—especially in the healthcare domain—at any time, within its reasonable discretion. That is, where licensing was concerned, the legislature taketh, and the legislature taketh away. The plaintiff naturopaths petitioned the US Supreme Court for review of the case and of the Tennessee Supreme Court’s holding on these constitutional issues. Review was denied. The table was set for a later broad assault on the licensing of natural healers across multiple states in the 1950s. 

And Repercussions The mischief and the stain originating in Tennessee spread quite quickly as well. In early 1947 as the scope of the Tennessee scandal was emerging and as the Tennessee legislature was repealing the Tennessee licensing law, investigations of licensing of naturopaths began first in Connecticut and then in South Carolina. In Connecticut, the state health commissioner—by state law a position held by an MD—withheld licenses from 28 applicants who had been approved for licensing by the Connecticut Board of Naturopathic Examiners starting in 1942 because none of the applicants had passed state licensing examinations, neither the basic science examination nor the naturopathic licensing examination. All of the applicants had been approved based on a Connecticut healing arts licensing reciprocity statute. All of the applicants sought reciprocity based on licenses issued in South Carolina—a state with no basic science examination. In 1946 three applicants brought suit in two actions against the health commissioner seeking a court order directing that their licenses be issued immediately (through a writ of mandamus or “mandate”).

Both applicants had failed the basic science examination more than once and then presented South Carolina licenses to the Connecticut Board, which had approved reciprocity applications. The applicants prevailed first in chancery (trial) court, then in the Connecticut Supreme Court. The courts—the chancery court in June 1946 and the Connecticut Supreme Court in April 1947—held that the health commissioner served in a ministerial capacity, that is, the health commissioner had no discretion in issuing licenses when the Naturopathic Board had approved the applications. The courts also found that the reciprocity statute allowed the approval without examination, but the Connecticut Supreme Court agreed with the trial court that the health commissioner was trying to protect the public interest. The Connecticut Supreme Court noted further that if evidence showed that the applications were fraudulent or the actions of the Board were taken in bad faith, members of the Board should be removed from office. Based on the issues developed in the court proceedings, the Connecticut police—which had the responsibility for licensing background checks—began an investigation into the reciprocity applications that lasted 6 months. This led in turn to an overlapping investigation by the state police in South Carolina. A clear pattern was documented: applicants from schools not recognized by South Carolina (which recognized only the National College of Chicago and Metropolitan of Cleveland as of 1947), primarily applicants with diplomas from Lust’s American College of New York, had obtained licenses in Tennessee between 1943 and 1946, and then been licensed in South Carolina without examination. Twenty-four applicants had then applied for licensing in Connecticut, again based on reciprocity. An investigation done in South Carolina by two Connecticut police detectives disclosed that only four applicants had actually spent any time practicing in South Carolina, and no time had been spent in Tennessee. The South Carolina Board had suspended the practice of accepting reciprocity applications from Tennessee in February 1947 when the Tennessee legislature outlawed naturopathy, but in 1947 and 1948, legislative pressure built up on the Board, and ND licensing in the state was under threat of repeal. By 1949 the repeal threat had been survived—for the present. Much of this was a result of Connecticut adopting a Basic Science Law when only National, Metropolitan, Western States, UNHA of Denver, and Los Angeles College—all chiropractic colleges with ND degree programs—had legitimate 4-year residency programs with a basic sciences curriculum. How had this been worked through by these colleges? By 1944 Dr. Budden’s view of the Oregon Basic Sciences Examining Board had changed based on 10 years of experience with the Board and its examinations. 

More Basic Science In the October 1944 issue of The National Chiropractic Journal, Budden offered his updated assessment of the Oregon Basic Science Law in the article “Effects of Basic Science Law in Oregon.” By this time, Budden noted that “we should like to make it clear … that we—the faculty and myself—have had some ten years of experience with the preparation of students for this test and, as a consequence, we feel that we make speak with some authority.” This notwithstanding that “public and candid discussion of the merits and demerits of basic science legislation has been regarded as a species of treason to Chiropractic (and Naturopathy).” But strictly directed to the Oregon experience, the Basic Science Law in general had shown his students to be ready join “one of the learned profession,” passing an examination given by a board of college and university professors chosen by the Board of Higher Education that “conducts its affairs with equity and intelligence (with) examinations

CHAPTER 4  that are fairly held and the papers fairly marked.” From all the evidence Budden had observed—and from a success rate of 25 out of 30 students passing the examination the first time (83.33%)—Budden believed “that if a student follows the courses covering the required subjects as they are given in the accredited schools, faithfully and with diligence he will pass the test.” He still noted that the public health part of the examination was based totally on the medical approach to the subject, requiring that the faculty had to teach students both “traditional” public health and the nonmedical alternative thinking. But he felt this was a price to pay in order that a higher level of nonmedical education was achieved, medical propaganda about a low level of nonmedical education was “wiped out,” success on the examinations favorably influenced the courts and the legislature, and there was more favorable treatment of the nonmedical professions by the outside the medical domain “all-around.” Finally, Budden noted that “of late efforts have been made to circumvent the law by setting up very dubious and possibly illegal ‘reciprocity.’” This, he said, was self-defeating: “There is only one way; to qualify enough candidates to show that the level of education makes two [licensing] examinations for the right to practice the healing arts preposterous.” In this thinking, as in many respects, Dr. Budden was almost 40 years ahead of his time. 

Dr. Schlichting Henry J. (Hank) Schlichting Jr. was born in Fowler, Kansas, in 1915 and was raised—or, as he put it, “reared”—in Weatherford, Oklahoma. By 1938, at age 23, he had graduated from Oklahoma City’s Carver Chiropractic College and relocated to Amarillo in the Texas Panhandle, where he joined “Dr. Roy G. Moore’s Chiropractic Hospital—Serving the Entire Southwest” as “Assistant Specializing in Dislocations and Fractures.” By the fall of 1941, he had relocated to Midland, Texas, and opened his own practice, the Modern Health Clinic. He advertised himself as “Dr. Henry Schlichting, Jr., Naturopathic Physician Specializing in Fractures and Dislocations.”138 How Schlichting came to call himself a naturopath is somewhat unclear. In the mid-1930s there was no licensing in Oklahoma or Texas for either chiropractors or naturopaths. Carver Chiropractic College in Oklahoma City taught obstetrics, minor surgery, and a broader use of adjustive technique than “straight” chiropractic. Texas was mostly dominated by straights through the influence of the Texas Chiropractic College in San Antonio. Although Schlichting’s early training was in chiropractic, and he was first in chiropractic practice in the Amarillo, Texas, area when he settled in Midland in 1941, he allied himself with the naturopaths in Texas and always called himself a naturopath.139 Also, by the fall of 1941, he had joined the newly formed ANA of Texas. At the organization’s first statewide convention in Dallas— attended by more than 500 initial members—he was elected secretary-treasurer. This quick ascension into the leadership ranks of the naturopaths of Texas led in turn to his connection with the western ANA group and with Robert V. Carroll.140

Dr. Schlichting and the Western ANA The 1942 convention of the ANA in Chicago was boycotted by Benedict Lust, Jesse Mercer Gehmann, T. J. Schippell, and their allies that became the eastern group. They held a “rump” convention of about 75 eastern naturopaths in Atlantic City in anticipation of the Chicago convention electing someone other than Lust as ANA president. In Chicago, Fredric Dugdale of Portland, Maine, was elected president. The president of the ANA of Texas, which since its formation in 1940 had delivered the biggest state representation to the ANA, was H. A. Brown of Canyon, Texas. He was elected first VP of

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the national ANA under Dugdale (Robert Carroll stayed as chairman of the Board of Directors), and in 1944 Brown was elected national president. When Carroll succeeded Brown as ANA president in 1946, he tapped Schlichting as his secretary.141 What made Schlichting stand out to Robert Carroll must be guessed at, but Carroll was a superb leader and organization man, and he recruited many significant naturopaths into the profession and into the western ANA. He recruited John Bastyr and many others in Washington State into naturopathy before moving on to the national stage. Schlichting had much to commend him: he became a strong ally of Harry Brown in the Texas ANA, an organization that grew to more than 400 members, most of whom also joined the national ANA; he was a talented writer and speaker; and he was a strong organization man. Once he was placed as national secretary by Carroll, Schlichting brought all of these talents to the national ANA. He continued to advance naturopathy in Texas, and he built a busy, thriving practice in Midland. Throughout the 1940s he advertised specializing in fractures and dislocations. Midland was a western Texas oil town, and oil roughneck work was notorious for its physical toll. The Carver techniques emphasized minor surgery and a “structural” approach to chiropractic. This became known in chiropractic as the Carver Technique, and as it evolved, it became one of the roots of naturopathic physical medicine.142 

More Background on Clinical Practice Willard Carver “opened the Carver-Denny School of Chiropractic in Oklahoma City in 1906, which in 1908 became the Carver Chiropractic College Carver’s philosophy gave equal importance to any anatomically produced ‘nerve occlusion,’ whether or not related to the vertebral column, while his structural approach to biomechanics became more ‘holistic’ than B.J.’s [Palmer] segmental one-bone-out-of-place approach.”143 Carver established four chiropractic schools, in New York City; Washington, D.C.; and Denver in addition to Oklahoma City. It was the Denver school that became most significant to natural healing education and clinical technique. As Walter Wardwell described the relevant history: “Homer G. Beatty (1897–1951), who had graduated from Carver’s Oklahoma school in 1922, became the dean of the Colorado school in 1923 and its president in 1924, serving until his death in 1951.” In 1939 Beatty published Anatomical Adjustive Technique. By 1935 the school was reorganized as the nonprofit University of the Natural Healing Arts, which offered three doctoral degrees, D.C., N.D. and D.P.T. [Doctor of Physical Therapy], the last requiring 3 years of study rather than the 4 required for the others.”144 Homer G. Beatty, DC, ND, is a part of the story of the professionalization of natural healing for several reasons. He was a part of the educational efforts of the National Chiropractic Association from its commencement in the early 1930s. He adopted the 4-year residency educational model for the UNHA DC and ND degree programs in lockstep with Budden at Western States. Although Colorado did not adopt licensure separately for NDs, his ND program at UNHA provided about half of the licensed NDs in the neighboring state of Utah by the mid-1950s. And perhaps most importantly, his book Anatomical Adjustive Technique, which described methods of treatment by manual adjustment for the entire anatomy, became a cornerstone for natural physical medicine. It was this type of clinical technique that was used by Schlichting in his West Texas practice. These clinical techniques were supplemented by the treatment methods illustrated in Alton Johnson’s Principles and Practice of Drugless Therapeutics, the first edition of which was also published in 1939. Johnson, another DC, ND, covered physiotherapy,

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electrotherapy, and hydrotherapy—in addition to adjustive technique—in his book on clinical science for natural healers. Both of these works were integrated by Budden into the postwar curriculum at Western States, and both Beatty and Johnson became members of the western ANA after the war. In Johnson’s case, he was recruited by Carroll and Schlichting to attend the 1948 western ANA convention in Salt Lake City and prevailed upon by them to accept the chairmanship of a new ANA committee on physiotherapy. In this position, Johnson wrote or edited a regular physiotherapy column in the journal of the association for several years (while also writing regularly for the journal The Scientific Chiropractor), and in the early 1950s he served a 3-year term on the national association’s Board of Directors.145 These were the clinical techniques at the center of Schlichting’s clinical practice during the 1940s when he established his practice and became a leader in the national movement of natural healers. He also became a civic leader in Midland, as a prototypical American joiner of voluntary civic associations: the Lions Club, the Jaycees, the Toastmasters, and various civic improvement efforts. Dr. Schlichting, or “Doc” to the citizens of Midland, practiced and lived very visibly in his adopted hometown, as many members of the western ANA did in the 1940s before natural healing came under assault by the AMA in the 1950s. 

Back to the National Scene As a national officer by 1946, Schlichting found himself in the middle of the dispute over control of the American Naturopathic Association, chartered in Washington, D.C. by Benedict Lust in 1919. After the “pseudo-group insurrection” of 1942, Lust remained embittered and denied the legitimacy of the “western ANA” until his death in August 1945. But for these 3 years, the nation was at war, and many were diverted from much of civilian life. The westerners largely built a communication network, held annual meetings, and waited out the war. Peacetime would come, and by circumstance, when it did, Benedict Lust had died. Then in peacetime, internecine warfare broke out among the naturopaths, as both Carroll and his western group and the eastern group led by Jesse Mercer Gehmann, T.M. Schippell, and a new face, Paul Wendel, laid claim to the “ANA.” Working with Carroll, Schlichting and a few others built up their Western “pseudogroup” while defending their right to being “the real ANA” and while constantly pushing the concept of unifying all naturopaths within one organization.146 Looking through the historical record, it seems clear that Robert Carroll had followed a methodical campaign to make the ANA into a true professional organization and that he had done so by amending the ANA constitution, bylaws, and governing structure. The western group had every right to be recognized as the legally constituted ANA organization as WWII ended, and Carroll’s ANA represented the broad-scope practitioners from the urban areas of about 20 states, including all of the licensed states. The eastern group that survived Lust, though, continued his dispute of their claim of legitimacy from 1946 to 1950, and the issue was a constant distraction.147 Through 1946 and 1947 the western group, for various reasons— including a postwar paper shortage—struggled to produce a monthly publication for its membership. During this time the leadership communicated with members through a series of “Dear Doctor” newsletters that Schlichting sent out from his Midland, Texas, office as “American Naturopathic Association, Inc., Office of the Secretary.” In January 1948, at long last the Journal of the ANA debuted, and the western ANA became a more established presence on the cultural, political, and professional scene. With much anticipation of a “Unity Convention,” the group convened in July 1948 in Salt Lake City,

Utah, for its annual meeting. Although the organization had grown in strength and presence—and more than 300 naturopaths attended the meeting from about 20 states—“unity” was not achieved, and Carroll passed the reins of the presidency to Schlichting.148 As of the summer of 1948, there were ND degree programs at National College of Chiropractic in Chicago, UNHA in Denver, Western States in Portland, and Metropolitan College in Cleveland, Ohio, that were legitimate 4-year residency colleges, as well as a program at the Los Angeles College of Chiropractic that was in a state of flux, although soon to be disbanded completely by the National Chiropractic Association. Schlichting took the presidency from Carroll at a time when the future for chiropractor-naturopaths looked promising.149 A historical note here is in order. Almost all of the naturopaths in the western group were chiropractors who had branched out in classic “mixer” fashion. With the exception of Robert Carroll himself, who had been a direct student of Henry Lindlahr and who had begun to call himself a “naturopath” instead of a drugless healer in the early 1930s, a historical tracking of every ND leader from the postwar era leads back to an early chiropractic college. As just two examples (Schlichting’s education has been covered), Harry Riley Spitler (the lead editor of Basic Naturopathy) graduated from Ross Chiropractic College in Fort Wayne, Indiana, before WWI, and John Bastyr (after whom today’s Bastyr University is named) graduated from the Seattle Chiropractic College in the early 1930s. Spitler was also on the faculty of the Metropolitan College from the mid-1930s until WWII. Also, in several states, “mixers” became identified as naturopaths because chiropractic “straights” took control of chiropractic licensing. Washington, South Carolina, Utah, and Texas were such states.150 

Dr. Schlichting Becomes President When Schlichting took over as president of the western ANA, things were at a critical juncture for natural healers, whether they identified as chiropractors or naturopaths both nationally or back home in Texas. Schlichting, while running a busy, growing practice and emerging as a civic leader in Midland, was up to the task of growing the ANA as an organization and achieving legal recognition for naturopaths in Texas. In doing so, he followed Robert Carroll’s model: practice openly and proudly as an “ND” and “Dr.,” be a civic leader, push constantly for recognition for naturopaths and legitimate ND school programs, and do everything possible to unify the profession within the ANA.151 As the incoming president in 1948, Schlichting had set the ANA 1949 convention for Houston, Texas, to take place coinciding with the opening of Houston’s newest—and in keeping with the mottos of Texas “biggest and best”—luxury hotel. As 200 Texas naturopaths joined with 200 out-of-state naturopaths for the ANA’s largest convention, Schlichting was able to announce to the attendees that the Texas legislature had passed a Texas licensing law as part of a legislative “deal,” and the governor of Texas was signing off on the legislation. Within 2 years, Texas was the home to more than 400 licensed NDs—the largest licensed state in terms of numbers and the largest source of Western ANA members.152 The nature of the “deal” became critical within just a few years. The Texas State Medical Association wanted Texas to adopt a Basic Science Law. The Texas chiropractors wanted a licensing law for “straight” chiropractic. An earlier law had been struck down by the Texas Supreme Court for violating a provision of the Texas Constitution that prohibited giving preference to any “school of medicine.” And the growing naturopathic group of 500 and counting wanted recognition. A group of legislators brokered a deal: a Basic Science Law would be adopted

CHAPTER 4  first; then, subject to it, a chiropractic law crafted to withstand challenge would be adopted; and finally, a pending naturopathic bill would be adopted.153 The Basic Science Law passed both houses of the Texas legislature handily, the chiropractic law was adopted by slightly tighter margins, and then the naturopathic law passed the state House fairly comfortably. But then, in a harbinger of things to come and with its Basic Science Law in hand, the state medical association tried to kill the deal with a push against the ND bill in the state Senate. The bill, after much delay, passed the state Senate by one vote, 23-22, in July 1949, while the profession was in Houston for its convention.154 

NATUROPATHS AT THEIR PEAK The Late 1940s and Professional Growth Under Schlichting’s leadership as national and state leader—and soon as a member of the first naturopathic licensing board in Texas— the profession continued to grow. But as noted earlier, the number of schools started to decline. Los Angeles dropped its program, and Metropolitan closed up in 1949. National dropped its program in 1950 under pressure from the National Chiropractic Association. Suddenly in 1951, Homer G. Beatty, DC, ND, of the UNHA in Denver passed away and with him, in short order, so did another ND program; only Western States under Dr. Budden was left.155 

In Memoriam—Robert V. Carroll, Sr. And then suddenly in March 1951, Robert V. Carroll—Schlichting’s mentor and the true “father” of the modern naturopathic profession passed away. As Schlichting and the editors of the Journal of the ANA memorialized Robert Carroll’s life and career156 In MEMORIAM Dr. Robert V. Carroll, Sr., died Friday, May 11th, of internal hemorrhage followed by coronary embolism. He died as he lived, suddenly and dramatically. There had been no prior illness. He went from excellent health to death in twenty-four hours. The naturopathic field has lost one of its greatest fighters. His was not the fight for individual stature; his was the fight for rightful and legal recognition of Naturopathy. He did not aspire to a statue, a pedestal or plaque exhorting his name in superlatives; his desire was to see naturopathy reach its honored place in the sun and to be a proud member of that profession. Now, his three score and ten has been completed. His earthly body has been laid away, but his spirit will march on. He has left a high mark on the wall. When we can measure up to it, his dream will have come true. The world has lost a man, the nation, a citizen, and naturopathy, a leader. But in our hearts each of us knows that the loss cannot be described in words alone. He admired and respected the qualities in others that fired them to opposition. In his heart he had only friends, agreeing friends and disagreeing friends. All will miss him. In the 1950s Henry Schlichting and the naturopaths faced challenging times that could not be foreseen in 1951. Robert Carroll’s leadership and vision would be missed. 

1947–1950 and Forward When Robert V. Carroll passed away unexpectedly in May of 1951, the natural healing profession that he had helped build with 20 years of diligent work was trending upward. When Dr. Carroll passed from the scene, national leadership was then held by Henry J. Schlichting Jr., of Midland, Texas, and by A.R. Hedges of Medford, Oregon. Educational

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leadership was in the hands of W. A. Budden of Western States College, Portland, Oregon, and Joseph Janse of National College of Chicago, Illinois. Texas had licensed naturopaths and chiropractors in 1949 as part of a legislative “deal” in which the Texas legislature also adopted a Basic Science Law. In 1950 the Georgia legislature had licensed naturopaths, and the Nevada legislature had also adopted licensing statutes in 1951. In the negative column at the time of Carroll’s passing, National College had dropped its formal ND degree program in 1950 under pressure from the National Chiropractic Association’s Council on Education, and the governor of the state of Nevada had vetoed the Nevada legislation just after the legislature adjourned. Joe Janse would proudly call himself a DC, ND, well into the 1960s and preside over a broad, “liberal” chiropractic curriculum at National, but the National College decision reduced legitimate, 4-year residency ND education to only Western States.157 In Texas, Henry Schlichting—“Doc” to the Midland, Texas, community—sat on a three-member naturopathic board that had processed and accepted more than 400 applications for licensing on a “grandfather” basis that was part of the 1949 legislation. Texas became both the largest state membership base for the western ANA and the largest licensed state in naturopathy. The natural healers seemed to have weathered the Tennessee scandal by 1951 and to have absorbed the lesson that H. Riley Spitler called “Remember Tennessee.”158 Naturopathy in Connecticut159 could have suffered much more than it did in the aftermath of the Tennessee scandal, but the Connecticut Supreme Court ruled in April 1947 that the Connecticut State Board of Naturopathic Examiners—not the state commissioner of health, a medical doctor—was the legal decision maker in licensing. As early as 1942 the health commissioner had delayed the issuing of licenses approved by the Board when the approval was under the licensing reciprocity statute and from South Carolina, a state with no Basic Science Law and that approved schools that were not on the Connecticut Board’s approved schools list. The commissioner’s position was that the reciprocity statue required licensing by a state with licensing requirements comparable to those in effect in Connecticut. By 1946, when this issue emerged into public awareness, licenses issued in Tennessee—where the diploma mill and licensing fraud scandal was first coming to light—also started appearing in reciprocity applications. By the time two applicants, both with diplomas from Lust’s American School in New York (which had lost its state charter in 1935) and with licenses from South Carolina and Tennessee, prevailed in the Connecticut Supreme Court, the legislature had repealed the reciprocity statutes at the urging of the governor, and the state attorney general had begun a review of all existing licenses to determine whether evidence of fraud existed in the application process. The Board revoked 17 licenses on its own, and the attorney general revoked several more after a trial that focused on the scandal in Tennessee and the loose practices in South Carolina in its own handling of the reciprocity issue. Extensive testimony was introduced by the attorney general’s office about the Tennessee licensing scandal from depositions taken in Tennessee, and also about the extent to which South Carolina “rubber stamped” reciprocity application in 1945 and 1946 supported by Tennessee licenses. In the long run, the Connecticut Board emerged with its licensing authority intact for applicants who graduated from properly approved schools and after successful passage of licensing examinations. The same proved to be true in South Carolina but only after the Board there went through a major legislative scrutiny process and adverse publicity of its own.160 During the 1947 South Carolina legislative session, the state House of Representatives passed a “concurrent resolution” asking

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for an inquiry into “examinations and personal qualifications required of applicants to practice naturopathy in this state and the propriety of granting licenses therefore.” During the 1948 legislative session, the full resolution was addressed between the House and the Senate (which was more favorable to the naturopaths), instructing the state Naturopathic Board to clean up its own house and report to the legislature by the 1949 session. As reported in the press, “The assembly … asked the State Board of Examiners to look into this situation, remedy it if possible.” In February 1949, the Board reported to the legislature “that it had revoked a number of reciprocity licenses, giving the holders a chance to regain them by taking state examinations … Most did and were relicensed … But at least one holder of a license refused to accept the board’s order and has brought court action against it.” The Board requested stricter licensing laws and stronger disciplinary powers, and the legislature obliged. 

After the Scandals These two states were the most directly affected by the Tennessee scandal. Connecticut was “purged” by the actions of state authorities; South Carolina was purged by aggressive action of the State Naturopathic Board. Licensing in both states survived the Tennessee infection. As a reflection of post-Tennessee reality, the 1949 licensing of naturopaths in Texas included a specific reference in its “grandfather” provisions that provided that licenses issued in the state of Tennessee were not to be considered for any purpose, recognizing that the Tennessee legislature had acted to invalidate any licenses that had been issued.161 With a substantial base to work with in Texas, Schlichting decided that the naturopaths should address their own education issues by establishing a legitimate 4-year residency college within the state to be supported primarily by the Texas profession. Lack of “Class A naturopathic colleges,” Schlichting wrote in announcing the founding of SCNM to the profession, “is a threat to the perpetuation of our profession.” In 1951 the Southern College of Naturopathic Medicine (SCNM) was chartered, and an agreement was made with the newly named Texas Southmost College—a 25-year-old institution previously known as Brownsville Junior College and located in Brownsville, Texas, to serve as the home for SCNM. The administrative offices for were located in a building on the Texas Southmost campus, and the premed and basic science courses for SCNM students were taken through cross-enrollment at Texas Southmost. The first major event sponsored by SCNM was a 2-week postgraduate seminar cosponsored with the Texas Naturopathic Physicians Association and held on the Texas Southmost campus.162 

A Change of Identity The summer of 1951 was eventful for the naturopaths for several reasons. Meeting in Miami Beach, Florida, the western ANA changed its name to the American Naturopathic Physicians and Surgeons Association (ANPSA), reelected Dr. Schlichting as its president, and established its corporate charter and located its headquarters in Des Moines, Iowa. The reasons behind this organizational restructuring were explained in articles by Schlichting and by A.R. Hedges in the September 1951 issue of what was now the Journal of the ANPSA. The changes were necessitated, they said, by the last resistance to the newly unified ANA continuing to lay claim to the name American Naturopathic Association. The group felt strong enough to take on a “post-Lustian” identity in representing the natural healing professions. Robert Carroll would likely have never accepted this one step. He proudly carried the banner of the ANA and felt—correctly—that he was entitled to do so. But Schlichting and Hedges felt that the profession could use the new strength that came with licensed status for

naturopaths in Texas, added to the existing licensed states, to support a modern profession, a reinvigorated educational system and a staunch commitment to the vital force. Carroll had always preached the value of science in explaining the theory of natural healing and the value of supporting work like Cannon’s vision of homeostasis. Schlichting preached the value of a professional identity as “family physicians” in a general family practice that included minor surgery and obstetrics. The new professional organization, he pointed out, was formed to “promote the public health and to perpetuate and advance the science, art and practice of the naturopathic school of medicine; to accomplish such objectives by attaining high standards of naturopathic education and by constantly stimulating and furthering the profession’s interest in and knowledge of the diagnosis, treatment and prevention of … disease and ill health.” As things trended upward for scientific natural healing in 1951, it was through this vision.163 

Medical Dominance Arises But all of this began to change dramatically in 1953, and what seemed so promising at the beginning of the 1950s was totally eroded by the end of the decade. No developments demonstrated this as much as the history of natural healing in Texas over just 10 short years. The force of medical dominance began to rear its head in 1953 at the annual convention of the AMA. A resolution was introduced by the Alabama delegation to the House of Delegates to attack chiropractic and naturopathy at their “weakest point,” their school and colleges. At the behest of AMA leadership, this topic was referred to the AMA educational committee rather than passed on by the House of Delegates. The educational committee felt that the AMA should refrain at the time from weighing in directly on the schools and colleges of other professions for political reasons, but the sentiment of the resolution was taken by AMA leadership as a strong interest by the medical profession in moving politically against these remaining “healing cults.” The matter was passed back to the state medical societies to deal with at the state level, with the full support of the national association.164 Historian Monte Poen called the AMA “the country’s richest and most influential post-World War II lobby.” In assessing the powerful effect of the AMA’s lobbying, Poen (from his research in the 1970s) noted that “As to the role played by organized medicine, I have become more impressed by the medical community’s ability to influence public opinion” in the post-WWII 1940s and 1950s.165 At the state level, organized medicine used its ability to influence public opinion to sway the views of mainstream newspapers, government officials, and state legislators. This was important because professional legitimization is established in the United States on a stateby-state basis. This has been true since 1889 when the US Supreme Court decided Dent v. West Virginia. The history of this first medical licensing case is the subject of James Mohr’s Licensed to Practice: The Supreme Court Defines the American Medical Profession.166 Dent, the petitioner in the case, was an Eclectic physician at a time in history when there were three schools of medicine: the Regulars (called “allopaths” according to Samuel Hahnemann), the homeopaths (as homeopathy was conceived by Hahnemann), and the Eclectics (which included the physio-medicalists). The Regulars in West Virginia founded the West Virginia Medical Society in 1867 and were the moving force behind the state licensing law adopted by the state legislature in 1882. By adopting legislation that required education at a Regular school, the licensing law barred practitioners from the two other schools of medicine from practicing in West Virginia. As David Korostyshevsky summarized the key aspects of the situation in his review of Mohr’s book in the Journal of the History of Medicine167:

CHAPTER 4  Grounding his analysis in both legal and medical historiographies, Mohr argues that while the American public supported public health efforts to control epidemic disease, medical licensing was not a popular reform. It was instead “a consciously engineered policy, drafted and passed through the concerted efforts of a specific subset of physicians, the elite Regulars” of the Medical Society of West Virginia (156 of Mohr). Mohr also challenges the interpretation that medical licensing was a response to the growing complexity of scientific medicine. Because scientific medicine did not produce tangible results until the 1930s, the push for medical licensing is a consequence of economic and political factors, not strictly scientific ones. Finally, Mohr shows that the Supreme Court upheld a version of medical licensing that relied on the quality of a physician’s education as the only measure of competence. Because the Regulars were the largest of the three schools of medicine in 19th-century America, the Dent decision allowed the Regulars to achieve the elimination of the two other schools on a state-by-state basis, which, by the early 20th century, went a long way toward eliminating the other schools. 

THE BEGINNING OF THE END The Texas Medical Wars All of this became relevant to events in Texas just as the naturopaths under Schlichting’s leadership had begun to achieve success professionally and to create an educational institution that would fill the void left by the NCA decision to require chiropractic schools to abandon the training of naturopaths. As Schlichting transferred the presidency of the ANPSA to Hedges in 1952, he focused even more on his position as secretary of the Texas State Naturopathic Examining Board.168 After Robert Carroll’s unexpected passing, Budden and Hedges further advanced natural healing in Oregon—and tried to secure natural healing throughout the Pacific NW. Schlichting tried to do so in Texas at the same time, hoping to secure the Southwest (Texas in addition to Arizona) for natural healing as well. The success of the naturopaths in Texas was targeted by the Texas Medical Association and the Texas Medical Board in 1953. The medical campaign against the naturopaths began in a remarkable way. When the 1949 legislature adopted the Texas Naturopathic Act (Article 4950d, Vernon Codified Statutes), its passage was during the term in office of Texas Attorney General Price Daniel (1947–1953). When Schlichting, as secretary of the Texas State Board of Naturopathic Examiners, sought guidance from the attorney general (AG) on the “grandfather clause” of the Naturopathic Act in 1952, that guidance was provided under AG Opinion V-1486, dated July 29, 1952, directed to Schlichting as a state official seeking a necessary interpretation of state law. Such guidance to state officials was—and is—a function of the AG’s office under the Texas Constitution and Texas law. In 1953 Price Daniel—later a US Senator (1953–1957), governor of Texas (1957–1963), and justice of the Texas Supreme Court (1971– 1978)—was succeeded as AG by John Ben Shepherd. Shepherd’s office received a letter requesting consideration of two questions challenging naturopathic validity under the Texas Constitution from the criminal district attorney of San Antonio, Texas.169 That district attorney was considering bringing action against naturopaths in Bexar County, Texas, if the Naturopathic Act should be invalid. This action was being requested by the county medical society and state medical association. In this situation, the Texas AG can—on a discretionary basis— serve a unique function, that of “an alternate Supreme Court.”170 This

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function is discretionary, but with the matter under consideration by a new AG, briefs were solicited by the AG’s office and submitted on the issue. In spite of “three very able briefs” arguing in favor of the enforceability of the Naturopathic Act, G Opinion S-60, dated June 29, 1953, was issued, finding the act to violate the Texas Constitution: “SUMMARY: The Naturopathic Act, Article 4590d. V.C.S. violates the provisions of Art. XVI, Sec. 31 of the Constitution of Texas in that it gives a preference to one segment of the healing arts. To rule otherwise would require a holding that the Act is uncertain and indefinite and thus unconstitutional. State Ex. Rel. Halsted, 182 S.W. 2d 479 (Tex. Crim. 1944).” The complete loss of naturopathy in Texas and the end of the Texas career of Henry J. (“Doc”) Schlichting Jr., ND, would not be final for another 5 years. But this was the beginning of the end, and in the next 5 years Georgia, South Carolina, Florida, and Utah would be lost as well. Medical dominance as wielded by organized medicine was under way. The fallout for naturopaths in Texas after the AG Opinion S-60 issued in July 1953 developed slowly at first. The 1953 session of the Texas legislature had just ended 2 months earlier, so there was no immediate opportunity to seek legislative relief. At the same time, although AG Opinion S-60 had considerable meaning, it was not the same as a decision by the courts. Schlichting and the Texas NDs worked quietly behind the scenes to take stock of the situation and to plan how to proceed. Judging by the material in the Journal of the ANPSA and the Texas newspapers, a decision was made by the Texas Naturopathic Physicians Association not to publicize the problems created for the Texas NDs by the attorney general’s opinion. 

Back to Education: WSC and Natura Medicina Events for naturopaths for the rest of 1953 largely took place outside of Texas. After the very successful ANPSA convention in Portland and the Western States commencement for the ND class of 1953, the news at the end of the year was the 5-years-in-the-making publication of Natura Medicina. Within the first year of work on Basic Naturopathy, it became apparent to the primary editors—H. Riley Spitler and Pers Nelson of Connecticut—that inclusion of medicinal substances used in naturopathy would need to be reserved for later so that Basic Naturopathy would be focused on and confined to theory. President Robert Carroll of the ANA appointed a committee in April of 1947 to prepare a textbook on medicinal substances in use in naturopathy. The committee was formally designated the Natura Medica, Formulary, and Therapeutics Committee. The committee first convened to arrange committee assignments at the 1947 convention in Detroit; A.W. KutsCheraux had been appointed committee chair. Originally the sections for inclusion were vitamins, cell salts, botanicals, and endocrines.171 Correspondence was sent out by the committee to gather information from “the men in the field,” as Kuts-Cheraux reported to the 1948 convention in Salt Lake City. Several complications that emerged from this survey of the profession were outlined by the committee chair in this report: (1) many of the botanicals in use had not been “subjected to the usual chemical analyses, alkaloid and glucoside determination … physiological properties and pharmacological action is very vague”; (2) many favorite botanicals had been identified by practitioners in “homely lay terms”; (3) “many agents endorsed by some practitioners were condemned by others as of no value”; and (4) a major issue that had not been “satisfactorily settled” had been the inclusion of Harrison Act narcotics that had been legalized by the Florida courts for use. Five more years would be required to bring all of the committee’s work to its fruition.

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The end product was worth the wait in general terms; the book was cutting edge in its contents and scope.172 In addition to Kuts-Cheraux, there were major contributions to the work by Dr. Herbert Clough on the formulary of selected botanicals and by Dr. Helena Winters of Kelso, Washington, on vitamins and tissue cell salts (with assistance from Dr. H. Riley Spitler, chief author of Basic Naturopathy). Reinforced by the entirety of the book’s approach to natural medicine was what had become the organizing philosophy of naturopaths in clinical practice: health and healing were emphasized rather than conventional medicine’s prevention and treatment of disease, the vital force and homeostasis were a critical core element of the philosophy, and suppressive pharmaceuticals with their side effects were to be avoided. But it arrived at an unfortunate time, just as the assault on naturopaths and chiropractors by organized medicine was getting under way. The textbook, for instance, arrived too late to be put into use at Western States during the 1953–1954 school year. Dr. Budden’s unexpected death in August 1954 kept the textbook from ever being incorporated into the curriculum. And as events would play out, this cutting-edge work arrived as the naturopathic profession was contracted severely by governmental action in the mid-1950s. When Dr. Budden passed away, a remarkable force of nature, a remarkable liberal chiropractor, and a great naturopath was lost to the world and to natural healing. The Journal of the National Chiropractic Association for September 1954 had “A Tribute” by J.J. (John) Nugent, DC, director of education: Dr. W. A. Budden, director of the Western States College of Chiropractic, Portland, Oregon, died suddenly in Portland on August 1, exactly one week after his return from a meeting of the Council on Education of the National Chiropractic Association. Dr. Budden was one of the pioneer leaders in chiropractic education … As much as any man in our profession, he espoused and introduced high educational standards in our schools. An important and forceful representative of our interests, his authoritative voice was respected and listened to in our legislative halls … To many, Dr. Budden’s passing will mean that a great chiropractor, thinker, and educator has passed into history. And it is so! He was one of chiropractic’s great … He was a vigorous and indomitable fighter for truth as he saw it for freedom of the individual, and, above all, for intellectual integrity … We will miss him sorely, the … profession has suffered an irreparable loss … Dr. Budden was born a gentleman, and lived and died by that high code. We shall not forget him! What was true for chiropractic was true for naturopathy as far as Dr. Budden’s career and commitment were concerned. Both professions owe a deep debt to Dr. Budden that should not be overlooked and certainly not forgotten. Events were building to a devastating outcome: the naturopaths were going to lose Western States College as an educational base and Texas as a professional base. When Dr. Budden died in August 1954, Western States itself was at a critical juncture. In the 6 months before Budden passed away, the three issues that would cause such trouble for Western States after his death had begun to appear on the horizon.

WSC and Hard Times First, the postwar boom fueled by the G.I. Bill was coming to an end. It is difficult to overstate the effect on the chiropractic colleges generally, and Western States specifically, of the G.I. Bill adopted by Congress as the Serviceman’s Readjustment Act of 1944. One of the main provisions of the act was the funding of higher education for those who elected this benefit. The funding available covered all of the costs of higher education: tuition, fees, and textbooks. This was true at public and private liberal arts universities and colleges but also true at WSC. By the time the act expired, almost 3 million veterans had attended institutions of higher education nationally, paid for by the federal government.173 Second, the new matriculation requirements that Budden had established at WSC and had convinced the Oregon legislature to put into law were taking effect. In an article entitled “The Aspects of Two Years Preprofessional Study as an Entrance Requirement,” published in the Journal of the National Chiropractic Association in March 1954, Budden noted that “economically, the schools … that follow the twoyear plan must expect to experience an, at least temporary, set back in revenue, and it would certainly be unwise … for an institution to venture in [this] direction unless its financial underpinning is of the caliber to absorb the shock through the lean years.” Third, the issue of Dr. Budden continuing the WSC of Naturopathy began to become a serious irritation within the Council on Education (COE) of the NCA. Indeed, there is every indication that only Dr. Budden’s personal standing within the NCA and the COE kept the issue from becoming a more persistent matter while he was alive. At the semiannual meeting of the COE held February 11 to 13, 1954, in San Antonio, Texas, Budden raised the subject himself. The minutes for Friday afternoon, February 12, 1954, reflect that “Dr. Budden asked for a frank and open discussion on the Naturopathic issue.”174 The conversation continued for the rest of the afternoon and again the next morning, as reflected in the minutes. Dr. John Nugent “reminded Dr. Budden that the Western States College was the only remaining school on the accredited list that still conducted a course in Naturopathy.” Dr. Budden set out his position on the matter. It was better to “sustain a reputable school of naturopathy” to establish an educational standard that legislatures could look to. Legislation in both Idaho and South Dakota that would have diluted educational standards substantially had been defeated by pointing to Western States as the baseline for naturopathic education. On that note, the afternoon adjournment was taken. When matters picked up the next morning, “Dr. Budden gave a complete review of the history of naturopathy and asked the Council to give him concise opinions and expression of decision” that he could share with the WSC Board of Directors so that “future policies of Western States College could be determined.” Budden was reminded that at the midyear meeting in 1950, both Dr. Janse of National, together with his administrator, and Dr. Budden had been told to discontinue courses in naturopathy. Dr. Budden’s Canadian protégé Dr. A.E. Homewood (dean of the Canadian Memorial College of Chiropractic [CMCC], chartered in 1945) “inquired as to the attitude of the Council” if the CMCC initiated courses in naturopathy “to accommodate those Provinces in Canada that sustained naturopathic laws?” Budden also inquired “whether the Council had the right to remove a college from the accredited list if it continued to conduct a naturopathic course?” 

WSC and the NCA The consensus of the council was stated as follows: (1) The Council “would frown on” the CMCC initiating any naturopathic courses, as

CHAPTER 4  a degree or otherwise; (2) Dr. Budden was advised to tell the directors of the Health Resource Foundation as the governors of WSC that “recommended that the course and school of naturopathy as conducted at Western States College be discontinued as soon as obligations and commitments could be fulfilled or terminated”; and (3) the council “does have the right to remove a college from the accredited list if a naturopathic program was operated concurrently with the chiropractic program at an accredited school.” Three weeks later Dr. Budden presided over the 1954 commencement for a class of four ND degree recipients and 26 DC degree recipients, 13 of whom also received the BTS degree.175 This was the state of matters when Dr. Budden passed away suddenly in August of that year—1954. 

Back to Texas In 1954 Schlichting left most of the national efforts to A.R. Hedges, who had the advantage of working from Oregon and so of having a stable licensing situation around him. The year was spent in Texas getting ready for the 1955 legislative session and weathering a summer of bad news that was beyond the profession’s immediate control. Harry Hoxsey was a controversial figure before naturopathy was licensed in Texas in 1949, if not widely known outside the Southwest. After being pursued in the Midwest and charged with practicing medicine without a license for the use of his Hoxsey cancer treatment, Hoxsey opened his Dallas cancer clinic, which grew to a substantial patient volume by the early 1950s.176

The Texas Medical Wars Relevant to naturopathy in Texas, Harry Hoxsey applied for licensing in 1950 under the grandfather provisions of the Texas law, and under the statute, he was deemed qualified to be licensed. First Carroll, and then Schlichting, kept Hoxsey away from the ANA/ANPSA, although Hoxsey had his supporters. But in 1954 when Hoxsey was in the national headlines and consistently reported on in the Dallas newspapers, he was called “the Dallas Naturopath who runs a cancer clinic,” and headlines like “Dallas Naturopath Enjoined from Claiming Cancer Cure” appeared. Hoxsey, with the backing of a Pennsylvania state senator, had opened a cancer treatment clinic in the Miners Hospital in Spangler, Pennsylvania. The facility was run by the United Mineworkers Union, and the senator was the hospital’s administrator. Convinced of Hoxsey’s success in cancer treatment the full backing of the facility was arranged. But at this point, the federal government moved in to bar the shipment of Hoxsey treatment preparations from Texas to Pennsylvania and the use of the “drugs” in that state. Several months of publicity about the legal dispute joined together “naturopath” and “fake cancer cure” in news coverage. None of this would prove helpful when the Texas legislature went into session in January 1955 and the Texas Naturopathic Physicians Association (TNPA) sought to have legislation passed that would overcome the AG’s objection to the naturopathic law adopted in 1949. The TNPA legislative committee under Schlichting’s chairmanship hired a well-placed executive secretary who had been the executive director of the Texas American Legion to pursue a legislative fix to the licensing situation. New legislation was prepared with the assistance of former legislators who were practicing attorneys with an eye to resolving the AG’s constitutional concerns. The legislation—House Bill 6—was introduced in the state House of Representatives in January at the start of the legislative session. It was quickly passed out of the House Public Health Committee, catching the medical profession offguard. Then, just as quickly, members of the House started receiving a “flood of protests [that] began to pile up on legislators’ desks.” In

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mid-February, the bill was sent to the State Affairs Committee by a 92-46 vote of the House, where the legislation died.177 

More Hard Times at WSC After Dr. Budden’s sudden passing, the leadership of the governing board of WSC—the Health Research Foundation (HRF)—fell to Dr. Milton Higgens of Couer d’Alene, Idaho. Dr. Higgens was himself a DC, ND, although Idaho had not licensed naturopaths. Dr. Higgens had been the Idaho representative to the NCA for several years and had been a friend and colleague of Dr. Budden and a director of the HRF for many years as well. Higgens realized in short order that the HRF would have to succeed Dr. Budden in setting WSC policy and that he would need to find someone to take over day-to-day management of WSC as well.178 In December 1954, Dr. Ralph Failor, DC, ND, a Portland-based alumnus of WSC (a class of 1953 member) signed on to do this job. As correspondence between Dr. Failor and Dr. Higgens demonstrates that Failor was established at WSC as more of a senior VP; he managed the college day to day on-site but with tightly constrained authority. He wrote full letters to Dr. Higgens once or twice a week and sought and accepted guidance from Dr. Higgens constantly. Dr. Higgens’s guidance came in responsive correspondence, also once or twice a week. The Failor–Higgens correspondence from December 1954 through April 1955, has three constant themes: on a day-to-day, week-to-week basis finances were very tight; the prospects for the future were very bleak; and the chiropractic and naturopathic professions were no help, although they were always “supportive”—lots of “thoughts and prayers.” The professions were particularly frustrating to Dr. Failor. As of April 1955, Dr. Failor had met with the “liberal” DCs of Oregon and Washington as well as the NDs from both states and the NDs from British Columbia. The DCs in Oregon were “supportive” but more concerned that the NCA needed to help the practicing profession more than anything. Legislative matters kept arising, and Dr. Budden was not around to address these anymore. The Washington NDs and “liberal,” NCA-connected DCs needed WSC’s structural appearance for their purposes, more than the actual institution; both professional groups needed to be able to cite WSC as the “model” for DC and ND education but took the existence of the college for granted. Nothing highlighted this more than a proposal from the Oregon NDs when Dr. Failor met with their leadership to ask for financial help. As communicated by Dr. Failor to Dr. Higgens: “They asked if we would accept money sufficient to put out a Naturopathic catalogue. I said yes we would. Then, they said, well that is contingent on your [sic] writing the catalogue as we want it written.” Meetings with the Washington NDs focused on the NDs submitting legislation that would use the WSC curriculum as an educational model. Dr. Failor had received contact from both the Florida and South Carolina ND Boards asking for catalogs from WSC to document that an ND educational institution did exist. Dr. Failor wrote to Dwight James, the national executive secretary, to clarify the situation; on behalf the national AANP, Mr. James offered “that the word phytotherapy instead of Herbology, and Naturopathic Medicine instead of non-medical was to be almost a must in the new issue [of the catalogue].” By the end of the spring term in 1955, Dr. Failor had become frustrated and dismayed by what he saw as WSC’s financial status and even more so with what he saw as WSC’s financial prognosis. As early as February 1955, Dr. Failor was recommending to the trustees of the Health Resource Foundation that governed WSC that the doors be closed, but the Board refused this assessment.

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As Western State’s historian Lester Lamm described the situation in the first academic year after Dr. Budden’s death: Unfortunately for Dr. Failor, he unknowingly accepted the leadership position at the beginning of one of the most troubling periods in the college’s history. The deluge of postwar students that created the boom period dried up overnight, leaving the college to face almost insurmountable financial difficulties. In response to student demands for a better education in better facilities, the college had moved to a new campus in 1947. It had retooled its curriculum, increased its admission requirements, added new faculty and staff, and assumed additional obligations in anticipation of a financially robust future. In short, by 1955, the college was overextended. The peak year of G.I. Bill college enrollment nationally was 1947. Across the country. institutions of higher education scrambled to accommodate demand, adding and improving facilitates and faculty. As Lamm noted, WSC was part of this great national response to a newly created marketplace for higher education that became a core piece of the postwar American middle class. This cumulative effect on Western States was borne out by a March 1955 report by Dr. Failor to the HRF Board: At a meeting of the board a month later, Dr. Failor shared a compilation of enrollment data from the previous four years. The trend was beyond alarming; it prognosticated doom. 1.1.1.1.1.1.1.1 1950–51 1.1.1.1.1.1.1.3 1951–52 1.1.1.1.1.1.1.5 1952–53 1.1.1.1.1.1.1.7 1953–54 1.1.1.1.1.1.1.9 Spring 1955

1.1.1.1.1.1.1.2 177 1.1.1.1.1.1.1.4 151 1.1.1.1.1.1.1.6 125 1.1.1.1.1.1.1.8 99 1.1.1.1.1.1.1.10 68

Only 24 students were projected to enroll in the fall class. The declining enrollment through 1953 to 1954 was consistent with the G.I. Bill wave effect, and by the fall of 1954, it was known that the G.I. Bill benefits were scheduled to expire in June 1956 and were not expected to be further extended by the Congress. This meant that students who enrolled after the fall term in 1952 would at some point have to pay their own way. For the entering class of 1954–1955 (the class of 1958), the numbers were further depressed by the new 2-year college attendance prerequisite. Dr. Failor reported that of 49 solid applications for admission in the fall term of 1954, 30 were advised that they did not meet the entrance requirements, and only 19 students could be accepted. 

Dr. Failor and WSC’s School of Naturopathy Some of this was undoubtedly foreseen by Dr. Budden, and it seemed like Dr. Budden had been forced to navigate the choppy seas of being a DC, ND “schoolman” for 25 years. What his plan might have been, though, no one seemed to know. The HRF Board was now two members who had worked with Dr. Budden for years plus Dr. Budden’s replacement directly recruited by Dr. Nugent of the Council of Education of the NCA. They continually instructed Dr. Failor to stay the course and carry out Dr. Budden’s vision. It was hard, though, for Dr. Failor to see the way. As Dr. Lamm reports: Dr. Failor met with a number of naturopathic trade organizations throughout the Pacific Northwest over the subsequent months to solicit support. Most in the naturopathic community voiced support of the college, but little in the way of direct financial backing ever materialized. What did materialize, however, was the naturopaths’ growing resentment for the lack of representation on the

HRF board and at the college. The naturopathic community had not gotten over being ignored when they first brought their concerns about equitable representation to Dr. Budden in 1948. Dr. Failor’s appeal to the naturopaths for support only widened the rift between the two disciplines. Dr. Budden had always been in a position to speak to the naturopaths as one of them. This personal relationship earned over 25 years was gone. Unlike 1948, Robert Carroll was not around to tell the naturopaths to “buck up” and support the only school that they had. In May 1955, matters came to a head at a special meeting of the HRF Board with the naturopaths of WSC, plus members of the naturopathic and chiropractic professions from Oregon, Washington, and British Columbia—those most affected by developments at WSC. This meeting followed a meeting on the evening of Thursday, May 12, 1955, of Dr. Failor, Dr. Higgens, and Dr. Williamson, the secretary of the HRF Board of Trustees. Also present by invitation were two well-placed DC, NDs, Drs. Ralph Hill and Ross Elliott. The discussion focused on the “paramount” financial issues: that monthly revenue was $4000, whereas expenses were $500; with faculty underpaid, fixed costs deemed “excessive,” and “old, delinquent accounts” also deemed excessive. Further discussed was that the HRF trustees were constantly accused of falsifying the financial status (i.e., “crying poor”), carrying out a “silence campaign” (i.e., refusing to provide specifics publicly), and that “Dr. Higgens was trying to close the College.” Also, the various DC and ND professional interests in Oregon and Washington were discussed as they affected WSC. These interests were summarized in the meeting minutes: “Chiropractic: O.A.C.P. Liberals—want controls; Advertisers—want controls; Straights—want no part; Naturopaths: Nature Group—want no part; Medical Group— want shots and medicine included in the Naturopathic Curriculum at College (Not permissible under our Charter.).” In short, the professional groups either wanted much more say where the college was concerned or had no interest in the affairs of the college. Drs. Higgens and Williamson decided, according to the minutes, to “call a meeting of the Full Board for Saturday, May 14th, 1955.” In addition to the HRF Board, it was determined that the professional groups, specifically including the OACP and “officials of the naturopathic Physicians,” would be invited to provide “council [sic] and suggestions.” On the afternoon of May 14, the meeting took place. Unfortunately, a reading of the minutes of the meeting can only be summarized as “things went badly.” 

Naturopathy in the Cross Hairs Dr. A.R. Hedges—then finishing his third year as the president of the national naturopaths (now named the American Association of Naturopathic Physicians [AANP])—could not attend due to a family illness. This was unfortunate, as from the notes of the meeting, it appeared that Dr. Higgens and Dr. Hedges got along, but most tellingly, it appeared that Dr. Higgens and Dr. Bleything did not—or at least that Dr. Bleything was suspicious of Dr. Higgens’s longtime membership in and connections with the NCA and Higgens’s friendship with Dr. John Nugent of the NCA. One of the issues that had the naturopaths most agitated was the attitude of the Council on Education of the NCA. As Dr. Lamm reports: Sensitive information contained in correspondence and conversations between WSC and the Council on Education had been leaked to the naturopaths. Most alarming to the naturopaths was the suggestion that WSC would be denied accreditation from NCE if it didn’t discontinue offering the ND degree … A letter from the CE was read to the attendees, which clearly described its position

CHAPTER 4  regarding the relationship between the two professions. Even though the letter contained no threat from the CE to deny WSC accreditation, it was clear a “divorce” was being encouraged. The attitude that drove the Council on education—made up of the other NCA “schoolmen”—was summarized by Dr. Higgens as “[the] Association felt that WSC was taking too many Chiropractic students and making Naturopaths of them.” Higgens told the naturopaths at the meeting that Dr. Nugent—even though as the director of education for the NCA he reported to the Council, and was therefore “the Messenger”—was “recommending against great pressure that we continue Naturopathy at WSC, is fighting the battle for us in the NCA.” And in fairness, Dr. Budden did not take chiropractic students and make them into naturopaths; he took students and made them into chiropractic and chiropractic-naturopathic physicians. And as Higgens told the meeting, there “is no difference between Chiropractic and naturopathy, in this state [Oregon] where most men have two licenses—most do not know which they are practicing under.” Events over the next year would bear out what Higgens said about Dr. Nugent. Although Dr. Nugent generally did not favor dual-degree programs, he had been a staunch friend and admirer of Dr. Budden as a schoolman and honored Dr. Budden’s vision after Budden was gone. The rest of the schoolmen on the NCA Council had tolerated Budden’s position while he was alive, on the Council and in their midst. They were not inclined to be tolerant after Dr. Budden could no longer argue the case himself. Bleything told Higgens at the meeting that if naturopaths were on the Board of the HRF and therefore had more say about the future of WSC, the naturopathic profession would contribute to the college. The overriding concern appearing in the meeting minutes was that the NCA Council would threaten to strip WSC’s accreditation unless the naturopathy program was dropped and that because the HRF Board was three chiropractors now, they would abandon the ND program if the threat was made. Higgens acknowledged that this could materialize as soon as the July NCA meeting. Bleything told the meeting, and Higgens, that if the HRF Board was expanded from three to five and the new seats were given to the naturopaths to fill, the naturopaths would commit financial resources to WSC, as the matter had been put before the Oregon Naturopathic Physicians Association, stating, “If Naturopathic profession gets representation on that Board you will get $10,000 without bowing to Nugent or anybody else.” Higgens was openly resistant to expanding the Board, but when the meeting ended at 5:45 that afternoon, the HRF founders group convened to Dr. Failor’s office, and by six they announced that they had voted to expand the HRF Board to five members, at least two DCs and two NDs. Dr. Higgens had become the dominant player in the present and future of WSC since the passing of Dr. Budden. He was dedicated to the continuing existence of Western States as a chiropractic college, accredited by the National Chiropractic Association. From his correspondence with Dr. Failor, it is apparent that although he had his own dedication to the School of Naturopathy, he had no expectations that the naturopathic profession would be of any financial help in the effort to keep the school open. He had learned through Dr. Failor’s efforts not to have expectations of the Oregon DCs as well. As an executive director of the NCA, he did have expectations of the NCA Council on Education and the NCA generally. Critical to him, as a result, was maintaining NCA accreditation. On June 4, 1955, the 46th Annual Commencement of the Western States College of Chiropractic and Naturopathy was held. In spite of financial pressures, WSC was still open, and in spite of the critical observations by the Council of the NCA, 22 doctor of chiropractic degrees

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and 1 doctor of naturopathy were awarded (along with three X-Ray Technician Certificates and two Laboratory Technician Certificates). The NCA met in early July, and although the Council minutes from that meeting reflect no on-the-record discussion of the WSC naturopathy program, immediately after the Council meeting, the HRF reversed itself and reinstated the three-member Board provision. For whatever reason, no financial commitment to WSC ever materialized from the naturopaths, and as of the 1955–1956 school year, the matter remained unresolved, with the naturopathy program under a cloud.   THE END Things remained as dire as they had been during the main school year as the summer term was to begin. Dr. Failor had advised Dr. Higgens in correspondence that Dr. Bleything would organize and run the summer term on a no-pay basis. Bleything and others who similarly volunteered taught the summer term, and on September 27, 1955, 13 of the DC graduates from June received their ND degrees, and the lone ND graduate from June—Canadian Robert Fleming—received his DC degree. But neither the school nor the naturopathy program was out of the woods. Dr. Lamm writes: By the July 23, 1955, meeting of the HRF board, it was apparent to the trustees that continuing an affiliation with the naturopaths would be problematic if WSC was to achieve accreditation. At the meeting it was said, ‘We are privileged to continue naturopathy… [until] we can gracefully work out a solution.’ … It was clear by the reaction of the naturopaths that financial support for the college would not be found with them. How or why this “was clear” based on events between May 19 and July 23 does not seem clear. It seems that before the addition of two new members to the Board could be implemented, and presumably based on issues that arose during the NCA meeting in Atlantic City, July 4–8, 1955, the Board withdrew the one condition that the naturopaths put on their financial support for WSC. (The minutes of the Council on Education meeting during this NCA annual convention do not reflect any on-the-record discussion of the naturopathy program. Dr. Failor was present and participated in the 3 days of Council meetings, which focused considerable attention to the 2-year college preparation admission requirement.) How or why the naturopaths let the established WSC naturopathy program be discontinued is lost in the fog of history. It is clear that the naturopaths associated with Western States trusted Dr. Budden and worked well with the Oregon Association of Chiropractic Physicians, the Oregon NCA affiliate. Indeed, as Dr. Higgens observed, the professions in Oregon had substantial overlapping membership. But Dr. Failor, as a DC, ND, asked for help that was not forthcoming: “Dr. Failor met with a number of naturopathic trade organizations throughout the Pacific Northwest over the subsequent months to solicit support. Most in the naturopathic community voiced support of the college, but little in the way of direct financial backing ever materialized.” So the determination of whether to continue the naturopathy program or not was left to the HRF Board and its dealings with the NCA Council, which was hostile to the naturopathy program. Again, in fairness, Dr. Higgens told the Washington NDs in January and again in March that they should dispatch a representative or representatives of their own to the NCA Council to present the naturopathy program as an integral part of Western States and ask that both WSC’s ND program and its accreditation be maintained as they had been during Dr. Budden’s lifetime. But they never did so. 

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The End, Part 2 Matters came to a head during the midyear NCA Council meeting in Toronto, Canada, February 15–17, 1956, as reflected in the meeting minutes. In September 1955, as the 1955–1956 school year had begun, Dr. Higgens had stepped in to try to at least stabilize WSC’s finances: In response to a clearly desperate situation and in an effort to bring about financial stability, Dr. Higgens stepped forward on Sept. 8, 1955, and committed his personal assets by securing a $39,000 mortgage on behalf of the college and took out a $10,000 life insurance policy, naming the college as beneficiary. This was not the first time Dr. Higgens had reached for his checkbook to rescue the college, nor would it be the last. Regardless of the deteriorating situation at the college, and perhaps in spite of it, he was committed to doing everything possible to guarantee survival of WSC. If WSC had been Dr. Budden’s school for 25 years, it was now firmly Dr. Higgens’s school, governed by him and the two fellow chiropractors on the HRF Board. At the meeting in May 1955, Dr. Higgens had been openly questioned about his personal commitment to continuing WSC as a School of Chiropractic and Naturopathy. By the time of the February 1956 NCA Council meeting, it seems apparent that Dr. Higgens’s commitment was to maintain an NCA-accredited School of Chiropractic, even—or perhaps especially—if that meant dropping the Naturopathy program at WSC. Although Dr. Failor, as the day-to-day manager of WSC in-the-trenches would have welcomed the financial support of the naturopaths and could have saved the Naturopathy program if support had been forthcoming, when support never materialized, the decision was really that of Dr. Higgens. The minutes of the February NCA Council meeting tell the story. Dr. Failor had advised that he could not attend and represent WSC “because of pressing responsibilities at the college.” And, one assumes, because of the cost of attending the meeting. The meeting was scheduled for 3 days, Wednesday, February 8, through Friday, February 10, 1956. The “first point of consideration placed before the Council from the prepared agenda was the matter of the Western States College of Portland, Oregon, still conducting a course in naturopathy” (emphasis provided). The Chair of the Council (Dr. Thure Peterson) read an “extended statement” prepared by Dr. Nugent and sent to Dr. Higgens “in relation to the matter.” The position set out in the statement was to advise Dr. Higgens and the HRF Board that the Council “considers it inopportune for any of the accredited colleges to seek to sustain a naturopathic course.” The Council further “encouraged the board to consider the necessity of discontinuing the course as soon as possible, even at cost and sacrifice of certain advantages that it might represent” (emphasis provided). Council member Dr. Hendricks noted that it was time for Western States to join Los Angeles and National and “discontinue its affiliations with the naturopathic profession.” Failure to do so “would constitute an embarrassment to the Council.” Then Dr. Nugent spoke, and it was apparent that he—regardless of personal feelings on naturopathic programs—felt bound to try to honor the lifelong commitment of his friend and colleague Dr. Budden: Dr. Nugent sought to advise the Council that relinquishing the naturopathic course by Western States College would impose on the college and its board of trustees tremendous economic problems and rob it of certain allegiance … It was the conviction of Dr. Nugent that a decision by Western States College to discontinue the naturopathic course would deal a severe blow to naturopathy and that unless the profession were to organize its own school it might well represent the demise of the profession …With Western States

out of the picture of naturopathic education only two schools would be left that issued naturopathic degrees and these were institutions of minor quality and influence; namely the Great lakes College of Mechanotherapy and in Dayton, Ohio, and Spitler College of Naturopathy in Eaton, Ohio. These observations by Dr. Nugent came straight from Dr. Budden’s long-stated positions expressed during many talks on the subject with Dr. Nugent and others in NCA leadership. In deference to Dr. Budden, Dr. Nugent set this entire argument out for the Council. He then communicated that these may not be the concerns of the current HRF Board governing WSC. Dr. Nugent told the Council that “upon the death of Dr. Budden, he [Dr. Nugent] had been asked by Dr. Higgens to help manage the Western States [College] and to help solve the naturopathic situation … that Dr. Higgens, personally, had invested thousands of dollars in the Western State College [because of his intimate friendship with Dr. Budden], yet he was ready to sacrifice the same if the naturopathic problem could be resolved; that he, Dr. Higgens, was anxious to have the Western States College sever its association with naturopathic education.” After all was considered “it was the general disposition of the Council that patience should be exercised in relation to the circumstances of Western State College,” as through “the death of Dr. Budden … the present administration and board of trustees of the college had inherited many compromising and not readily solved problems.” Dr. Nugent advised the Council that he was certain that before the Council meetings concluded, “he would obtain word that “a definite decision to eliminate the naturopathic course at Western States had been consummated.” 

And Naturopathy Is Finished at WSC And so it was. As the Council convened on the morning of Friday, February 10, the Council was to hear the report of the Council on Educational Standards (Accrediting Committee). The Accrediting Committee proposed that the Council adopt a resolution that Western States “beginning September 1, 1956 … should seek to discontinue students for training in naturopathy” and “terminate its commitment to those naturopathic students enrolled.” Dr. Nugent advised that he had spoken several times to Drs. Higgens and Failor since Wednesday morning, and that they understood that this step would be necessary “although it would involve extended financial loss and … the college might not be able to survive.” Further that they had announced the day before during an all-school meeting that the decision had been made to discontinue the naturopathic course.” The Council meeting minutes note that the Council had received a copy of “A Statement of Policy on Western States College” that constituted the formal announcement of the decision to all concerned, and that the Council had responded through the Council secretary, Dr. Janse, acknowledging the “courage and integrity” that this decision had required. Within a short period of time, the naturopaths associated with Western States determined to start an independent naturopathy program, initially intended to provide an ND program for WSC’s DC graduates who were desirous of an ND degree. In July, three NDs previously associated with WSC, Drs. Bleything, Spaulding, and Stone, chartered an Oregon not-for-profit corporation, the National College of Naturopathic Medicine (NCNM). But this separation was the kind of “divorce” that left both parties worse off. Dr. Higgens had clearly hoped that the NCA would lend financial assistance to WSC with the “naturopathic issue” resolved. Instead, WSC suffered a severe enrollment decline and financial distress for almost 15 years, with average DC class sizes of 12 to 15 and a total enrollment of 50 to 60. The NCA responded with “hopes and

CHAPTER 4  prayers,” restricted accreditation, and suggestions that WSC should be merged with either Los Angeles or National—the two stronger programs with which they had a historical affinity. Meantime, the NCNM proved to be a difficult proposition, as the ND profession of Oregon, Washington, and British Columbia tried to build a 4-year residency program. It was 15 years before the program— moved to Seattle in terms of actual facilities—began to have decent attendance in the early 1970s. And all of this had taken its toll on Dr. Failor, DC, ND, as well. As Dr. Lamm reports: Dr. Failor approached the Oregon Association of Chiropractic Physicians (OACP) with his doubts that the college could survive beyond July 1, 1956. The total student population was 73 and a number of disgruntled students announced their plans to transfer to the new naturopathic program starting in the fall. Dr. Higgins appealed to the National Chiropractic Association to support a policy compelling all chiropractic colleges to adopt a two-year, pre-professional college education admissions requirement. The NCA refused to budge. By summer 1956, frustration with lack of support from the NCA, CE, OACP, NDs and DCs; compounded by the student, staff and faculty discontent on campus and a worsening financial situation at the college was more than Dr. Failor was willing to tolerate any longer. He submitted his letter of resignation to the HRF. Even though he had repeatedly recommended closure of the college and left the institution saddened and disappointed, he was effective in instituting stopgap measures that kept the college solvent. Without Dr. Failor’s efforts, the college would have closed. The educational structure of naturopaths had been severely damaged. And in Texas, the profession began to suffer damage as well. 

Back to the Texas Medical Wars The full story of the 1955 Texas legislative session where the naturopaths were concerned would not be told until the legislature reconvened in 1957, but by now, it had become well known that the AG had determined the old law unconstitutional. After the legislature recessed without action, the state comptroller refused to pay any further warrants issued by the existing Naturopathic Examining Board given the AG’s ruling, effectively putting the Board out of business.179 In January 1956, using legal counsel retained by the TNPA, the Board filed suit against the comptroller asking the court to uphold the statute and order the comptroller to pay its bills. In May 1956, the district court judge hearing the case ruled in favor of the Naturopathic Examining Board and against the comptroller represented by the AG. The district court upheld the statute as constitutional as to the licensing and registration of naturopaths and directed the payment of warrants issued by the Board. The comptroller’s office filed an appeal, and the matter began working its way through the Texas appellate courts. In 1957 matters played themselves out badly for the Texas naturopaths in a very public way.180 The 1957 Texas legislative session began in late January 1957. At the time, the appellate case on the constitutionality of the 1949 statute was pending. Henry Schlichting had been succeeded as president of the TNPA by Howard Harman of San Antonio. The naturopaths were trying in this session to once again get legislation passed that would deal with the AG’s opinion. At the end of February, Dr. Harmon went to the Speaker of the Texas House of Representatives with a tape recording on which a member of the Texas House appeared to solicit a bribe to withdraw legislation that would repeal the 1949 law and ban naturopaths from practicing in Texas.

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This led to House investigative committee proceedings, a grand jury investigation, an indictment against the legislator, and the legislator’s conviction. All of this played out between March 1957 and September 1957, with constant newspaper coverage throughout the state of Texas. It also had two unfortunate effects: few legislators wanted to have anything to do with the naturopaths while this was going on, and first the House investigative committee and then the grand jury dug up the story of the naturopaths’ activities during the 1955 legislative session. What emerged was that the naturopaths had raised a “war chest” of as much as $52,000 for the 1955 session and had spread around among members of the legislature perhaps as much as $37,000 or more to try to get legislation passed. In 2018 dollars, this would be $480,000 dollars raised and $345,000 passed out in legislative “cash gifts.” It was rumors of this type of largesse that drew the interest of a young member of the House of Representatives to Harmon as TNPA president while he was in Austin—the state capital—for the 1957 session. The bribe solicited was $5000 total, $3000 for the representative and $2000 to share “with others.” In 2018 dollars, this would be $45,000 total, $28,000 for the representative, and $17,000 to “share.” The naturopath caught up in the inquiry into the 1955 legislative activities of the Texas Naturopathic Physicians Association was Henry J. Schlichting Jr.

Texas Medical Wars Continued—1957 While the 1957 Texas legislative fireworks were playing out, the legal process was playing out at the same time.181 In late January 1957, as the legislative session was getting under way, the Texas Court of Appeals upheld the AG’s opinion and reversed the district court. The court held that the 1949 Naturopathic Act was unconstitutional, as the AG’s opinion had concluded. The legal effect, as stated by the court, was to completely undo the legislative gains that the naturopaths had been granted under the 1949 “deal” that had given the medical profession a Basic Science Law: “The judgment of the Trial Court is reversed and judgment is here rendered declaring the Naturopathy Act, Art. 4590d V.A.C.S., void” (emphasis provided). In February, Dr. Howard Harmon of the Texas Naturopathic Physicians Association tape-recorded House of Representatives member James Cox soliciting a bribe and took the recording to the Speaker of the House. In March, a legislative investigative committee was convened by the Speaker and—after an emotional “farewell” address to the House—Cox tendered his resignation, which was accepted by the governor. In April, a grand jury was convened, which took testimony about the bribe allegations and also about another matter that had emerged during the legislative hearing: allegations of a “slush fund” that had been used by the TNPA during the 1955 legislative session to “educate” House members with regard to legislation proposed by the TNPA after the AG’s opinion had been issued in 1953. If these assertions about the size of the “slush fund” and the extent of “educational” efforts were true, it had been for naught in 1955. The remedial legislation had been reported out of the House Public Health Committee early in the 1955 session—allegedly as a result of the TNPA “education” efforts—only to die before going any further. When the bill was quickly pushed through the committee process, the medical association took note, and before the matter could come to the House floor for a vote, a “flood of protests” from MDs “began to pile up on legislator’s desks,” and the bill stalled. As the House investigation was proceeding in April, the statements of a “mystery witness” were produced by the Texas Department of Public Safety (DPS). The committee abruptly stopped its hearings and referred the matter to the grand jury. In mid-April, the grand jury heard from other NDs appearing before them about the “mystery witness,” who was identified as Henry Schlichting Jr. Other NDs told the

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press that “Schlichting was the only person who knew how the association’s money was spent during past sessions of the legislature.” On April 30, 1957, the grand jury heard from Schlichting, who had given a lengthy interview and sworn statement to the Texas DPS the week before. After his appearance, Schlichting steadfastly gave “no comment” statements to the press, and never did he disclose what he testified to, nor the details of what the TNPA had done with its “slush funds” and “educational” efforts over many years. Another ND who appeared before the grand jury told the press that Schlichting “held his hand on the purse strings since 1943 and still does [in 1957].” But whatever Schlichting disclosed to DPS investigators and the grand jury in March and April of 1957, no indictments were ever issued against anyone accept Representative Cox for soliciting the bribe from Dr. Harmon. But the entire Harmon–Cox–naturopaths bribery affair had a dampening effect on both the 1957 legislative session and the naturopaths as an interest group desperately needing legislative action. In an extensive two-part investigative report,182 a reporter for the El Paso Herald-Post noted for the “Frantic Fifty-Fifth” legislative session that lobbyists had gone into hibernation when “the naturopaths got cute with their tape recorders” as the legislature began “shaking with a severe case of capital J jitters resulting from the naturopath tape recording in the Representative Cox bribery scandal.” Just as significant for the naturopaths was the direct effect on them: You won’t find any naturopaths trying to influence legislation during these nervous days. They’re now on the inactive list as far as lobbying is concerned—maybe because they figure they’ve raised their share of turmoil this session, or because they’re too busy testifying before the Travis County Grand Jury, whose deliberations are being watched with such big interest by the legislators … Dr. Howard Harmon, the naturopath lobbyist whose tape recording brought about the Cox indictment, hasn’t eased the situation any with his forecast that half a dozen lawmakers besides Representative Cox have ample reason to worry.183 In so many ways, these developments could not have come at a worse time for the naturopaths in Texas. On May 1, 1957—the day after Schlichting appeared before the grand jury as the “mystery witness”— the Texas Supreme Court refused to hear the writ of error (appeal) by the Naturopathic Board of Examiners from the court of appeals decision against the 1949 Naturopathy Act. On June 12, 1957, the Texas Supreme Court rejected a request for rehearing of the application for a writ of error, leaving the naturopaths without any further relief at the state-court level. Within 60 days, the naturopaths applied for relief from the US Supreme Court; throughout these various legal steps, the Texas courts stayed enforcement of practicing medicine violations pending the final legal determination of the validity of the 1949 law. In October, former representative Cox went on trial for bribery, and the newspapers throughout the state had the naturopaths on the front pages again. After the testimony of Dr. Harman and the playing of the recording that Harman had produced, Cox was found guilty as charged. On November 12, 1957 the US Supreme Court declined review of the Texas court decisions on the 1949 naturopathy law. 

Texas—The End On December 3, a massive statewide series of legal actions was taken across 27 Texas counties184 coordinated by the Texas AG, who vowed to “run the naturopaths out of Texas.” In the first “test case” arising out these actions taken in the name of the Texas State Board of Medical Examiners, an injunction was entered on December 9 against Henry Schlichting, enjoining him from continuing to practice naturopathy in the state of Texas without a license to practice medicine. Multiple other

injunctions were entered against naturopaths in other counties across the state. For good measure, the AG asked for—and received—an injunction against the continued existence and activities of the Texas Naturopathic Physicians Association.185 The naturopaths in Texas—about 450 of them—were in fact out of business. The case against Schlichting was appealed, and an accelerated review was granted by the Texas Supreme Court. Arguments were heard by the court in January 1958, and a decision was handed down on February 19, 1958. The Texas Supreme Court upheld the injunction against Schlichting. The US Supreme Court later denied review. The Texas career of Dr. Henry J. Schlichting Jr., naturopathic physician, was over.186 Schlichting stayed on in Midland, where he had built a solid reputation as a citizen, for another 7 years, practicing as an audiologist working for one of the largest hearing aid companies in the United States. His hearing clinics were regularly advertised, and his appearances at out-of-state gatherings of naturopaths were mentioned in the Midland and Pacific NW newspapers. Then, in 1965, he left his adopted home state of Texas and established a naturopathic practice in Phoenix, Arizona. In 1973 at the age of only 58, he died suddenly at home on a Sunday afternoon. He was taken back “home” to Midland as his resting place.187 

Three More States Fall: 1955 to 1957 With both WDC and the state of Texas lost to naturopathy, the decline of natural healing accelerated. Licensing was lost in Georgia and in South Carolina, both in 1956. In Utah and Florida—after an extensive review of the profession and its lack of educational institutions—prohibitions were put in place against any further issue of licenses as of 1957. In Florida, after a successful court challenge to the initial action, new legislation was passed in 1959 reinstating the ban on further licenses. In all of these cases, three issues turned the tide against naturopaths: no legitimate school, declining numbers nationally (from no new graduates and 450 licenses gone in Texas), and intense opposition to natural healing by the AMA and its state constituencies. Naturopaths were first licensed in Florida in 1927.188 At that time, Benedict Lust had for some years operated his second Yungborn Sanitarium in Tangerine, Florida, in the Tampa Bay region of the state. The legislation adopted defined naturopathy as a “drugless” law, consistent with pre-1939 concepts of that term: “The use and practice of psychological, mechanical and material health sciences to aid in purifying, cleansing and normalizing human tissues for preservation or restoration of health … employs heat, light, water, electricity, psychology, diet, massage and other manipulative methods.” Naturopaths were licensed in South Carolina in 1937 under the leadership of M. S. Dantzler of Spartanburg. South Carolina was a state where the early chiropractic movement was dominated by “straights,” and the “mixers” became naturopaths to achieve their own identity before the legislature. The original 1937 law was modeled directly after the Florida statute. (“The use and practice of psychological, mechanical and material health sciences to aid in purifying, cleansing and normalizing human tissues for preservation or restoration of health … employs heat, light, water, electricity, psychology, diet, massage and other manipulative methods”).189 In 1941—on the eve of WWII—the statute was amended with this addition: “The use and practice of phytotherapy, minor surgery, obstetrics and gynecology, autotherapy and biologicals shall be a part of and included in the practice of naturopathy.” The difficulties weathered by naturopaths in South Carolina from 1947 to 1949 after the Tennessee scandal have been discussed. Significantly, these problems were resolved by giving the state Board more enforcement powers so that the Board could better police the profession. 

CHAPTER 4 

The Florida Saga Begins In Florida, naturopaths in the greater Miami area of the state pushed to have the law interpreted to allow the right to prescribe drugs after the 1939 regulations were put in place at the federal level. Using the courts, this effort was successful in 1947 in convincing the Florida Supreme Court to interpret the reference to “phytotherapy” in the Florida statutes to include all drugs derived in any way from plant origins, including morphine and opium derivatives. In 1949 this created a significant—and predictable—backlash.190 In early April 1949, the State Board of Health, through its five-member governing body, adopted a resolution urging legislative action regarding “the licensing and practice of naturopathic physicians,” with a finding that: “The board has information that the practice of naturopathy including the licensing of naturopathic physicians, and the treatment of patients of licensed naturopathic physicians is being conducted in such a manner as to be detrimental to the public health of Florida.” The next day, legislation was introduced in the Florida Senate to make the practice of naturopathy unlawful in the state, and the bill was referred to the Senate Committee on Public Health. Pending the hearing by the committee on the bill, the State Health Officer, a medical doctor, picked up the attack on licensed naturopaths, who at the time numbered 239. The concerns expressed were that naturopaths had been “drugless physicians” who opposed drugs as contrary to the natural maintenance of health and natural methods of healing, that naturopaths had no training in the use of materia medica, that no other state allowed such practices by naturopaths, and that the state of Tennessee had just determined that much of naturopathic education was a fraud, yet some Tennessee licensees were among the NDs in Florida now using drugs. On April 19, 1949, the Florida Naturopathic Physicians Association ran a quarter-page ad in the Miami Herald, Florida’s largest newspaper. The ad was entitled “NATUROPATHS ANSWER THE ATTACKS OF THE STATE BOARD OF HEALTH, An Open Letter to: Wilson T. Sowder, M.D., State Health Officer.” In this “open letter,” the NDs defended their record of having “used narcotic drugs under Federal Government regulation [for] several years during which they did not abuse or misuse the privilege.” The letter further defended the way in which NDs designated their practices; conformed to the laws, including the court decisions on prescription authority and naturopathic educational standards established under the law; and questioned the good faith of an MD as “promoting monopolistic legislation … of the American Medical Association” rather than serving “the people of Florida.” The Senate committee held an all-day hearing the next day and heard a carefully marshaled presentation on these issues, including hearing the testimony of Harry Avery—the Tennessee investigator— as well as a state narcotics investigator and a regional federal narcotics inspector. The naturopaths were represented by legal counsel who was allowed to question the witnesses who appeared. More than 100 NDs attended the session. Although both narcotics inspectors argued against the NDs having prescription authority, both acknowledged under questioning that there had been no reported narcotic violations against Florida naturopaths. As the hearing closed, the sentiment of the committee seemed to be that although tighter regulation would be in order, the bill outlawing naturopathy was too much. But the record was mixed. Most of the NDs had been licensed before the Basic Science Law had been adopted. Of the 239 licensees only 22—all from National College in Chicago— had passed the BSL examination. Many practitioners had diplomas from Lust’s American College of Naturopathy; it was admitted into the record that Lust had been charged in 1934 with operating an unchartered school in New York. As the hearing closed, the committee chair

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put into the record a stack of 700 telegrams and 50 letters opposing the bill and 5 letters supporting the bill. The committee voted at about 8 o’clock in the evening to not report the bill out to the Senate by a vote of two “for” and seven “against.” One takeaway was important, though: one of the “for” votes was from State Senator Leroy Collins of Tallahassee. In the late 1950s, Collins was to become Florida’s governor.191 The staff reporter who covered the hearings—indeed, the story of the Board of Health position on naturopaths—also contributed a lengthy four-part series on naturopaths in Florida. The one school represented in Florida among the licensed NDs that was clearly legitimate was the National College of Drugless Physicians—the Lindlahr school— founded in 1908 and part of the National College of Chiropractic. About 40 alumni were practicing in Florida, and “even the critical state medical societies that have commented on naturopathic schools don’t charge that this college doesn’t offer full four-year training, even though they do complain that it does not offer a four-year course devoted exclusively to naturopathy” (emphasis provided).192 At the conclusion of the reporting on the legislative matters and the general investigation of naturopaths in Florida, the reporter concluded the series with these observations: “Better regulation, rather than prohibition is probably the answer. If naturopaths were not permitted … drugs; … prominently identified themselves as naturopaths; if stricter examination of schools … [was] required—the public and naturopathy would be benefitted.”

The Three-State Region Geographically Georgia and South Carolina share a long common border, South Carolina to the east and Georgia to the west. The common border cuts a line through a common rural area. The Georgia newspapers covered the reports out of South Carolina through the 1947 to 1949 events, and in 1950, the Georgia naturopaths had general legislative support built up for establishing a licensing board that could “cull the quacks” from the state. The acceptance of this idea in South Carolina was noted, and the Georgia legislature followed suit. Then in 1955, issues arose in both South Carolina and Florida. Geographically “in the middle,” Georgia was affected as well. The South Carolina issues started when the state AG ruled that the law did not allow the naturopaths to prescribe drugs, specifically plant-based narcotics such as opium derivatives. The NDs frankly pushed things too far when they took the AG to court over the issue. Although they won the first rounds of the legal battle, the state medical association used the prospect of NDs claiming prescriptions rights, including to narcotics, to raise the issue of these practices being a threat to public safety.193 The prescription of such plant-related drugs had first arisen in Florida in the 1940s, and the courts in Florida had held that the NDs had these prescription rights. But this issue raised conflict in Florida in 1955 as well through a series of investigative articles in the Miami Daily News entitled “Who Are the Naturopaths?” The articles—four in number—raised the same questions being raised in the South Carolina legislature: Where did these naturopaths go to school, and how has it come to pass that they can prescribe drugs and do minor surgery?194 In South Carolina and Florida, these questions in 1955 and 1956 provoked no acceptable answers. The National College program had been closed in 1950, the Western States program in early 1956. After the scare in 1949, the Florida NDs went on with business as usual. In fact, when the 1955 Miami News investigation was reported in November 1955, the only school pointed to by the Examining Board as approved was Western States. Then the program was discontinued in February 1956. Leroy Collins was now the governor of Florida, and the Miami News investigation called him out by name for his legislative opposition to

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naturopaths in Florida. Governor Collins commissioned a report from the State Bureau of Narcotics on the state of naturopathy. When the report documented that things had not seemed to have changed since 1949, he announced that one of his legislative priorities for 1957 was outlawing naturopathy in Florida.195 In 1955 South Carolina outlawed naturopathy; in 1956 Georgia outlawed naturopathy; in 1957 Florida outlawed the issuing of any new licenses to practice naturopathy. When the original legislation was struck down by the Florida courts, the 1959 legislature renewed the ban on issuing further licenses. Ultimately, the bans in these three states and Texas were upheld by the courts as within the police powers of state legislatures. In the meantime, things were not going well out West either. 

Utah

The Early Days In Utah the authorization to legally practice naturopathy first appeared in 1925 when the legislature passed legal authority for an examining board for physiotherapy and naturopathy under the Utah Department of Registration.196 The governor at the time vetoed the measure on the basis that such practices were authorized to be licensed under the state medical board as treatment by a practitioner without the use of medicine or surgery. In October 1934, there were 15 naturopaths registered with the Department of Registration through the authorization of the medical board. Finally in 1937, a separate naturopathic board was authorized by the legislature, and the legislation was signed into law this time around. In 1939 legislation was passed into law raising the educational standards for naturopaths to require 4 years of post–high school education. In each legislative session after 1939—1941, 1943, and 1945—legislation was proposed but not passed to allow for “practicing as a naturopathic physician and surgeon, including obstetrics.” But in 1946, it emerged that the naturopathic examining board had been conducting a supplemental examination for obstetrics and minor surgery in addition to a basic naturopathy examination just as the medical board had done before the examination authority had been transferred. These supplemental licenses were then issued by the Department of Registration to license holders. 

Utah Opens Up This only became publicly known in September 1946, when a second AG opinion issued in May 1946, was publicly issued and reported by the Utah newspapers.197 The story was this: In January 1946, a new department director had asked for an opinion from the AG whether naturopaths could be licensed to practice surgery and obstetrics. The AG’s Letter of Opinion answered the question no, as both surgery and obstetrics were the practice of medicine, not naturopathy. In so answering, the opinion noted that there was no such thing as “minor surgery”; under Utah law, surgery was surgery. In May, a second AG opinion letter was sent to the Department of Registration with the recognition that since 1939, naturopaths had been examined in “minor surgery and obstetrics,” and upon successful passing of the tests, they had been issued licenses to practice. This opinion noted that the statutes “were not free of ambiguity,” and therefore the practice of the Department would be deemed an existing “administrative interpretation” of the law, effective until either the legislature modified the statutes or the courts ruled otherwise. Moreover, the opinion went on to state that although licensed naturopaths could not use or prescribe drugs, those licensed to practice obstetrics and surgery could use and prescribe those drugs that “were recognized requirements in obstetrics or minor surgery.” The opinion further stated that although naturopaths could not use drugs in general practice, they could keep on hand or prescribe drugs for communicable diseases or emergencies (e.g., antidotes for poisons) in practice.

And so, as a matter of statutory interpretation, Utah became a state that allowed very broad practices to naturopaths. The legislature never did adopt any statutory language that modified the statutes interpreted by the AG, and the courts never reviewed the matter; this was the status quo until September 1955. In 1955 the Utah Board of Health—not the Department of Registration—requested a new AG opinion on the same statutory issues. At the time, the Department of Registration listed 82 naturopaths, of whom 66 were authorized for obstetrics and minor surgery.198 

And Shuts Down Again The 1955 AG opinion reviewed the same licensing statutes as the 1946 opinions and came to a completely different conclusion. Naturopaths could not be licensed to do obstetrics and minor surgery nor prescribe drugs. Under this new opinion, the Department gave notice in November 1955 that it would be canceling all of the licenses issued to naturopaths to practice obstetrics and minor surgery, effective January 1, 1956. The naturopaths appealed to the courts but lost before the Utah Supreme Court in June 1956.199 In the 1957 legislative session, legislation was passed that would have allowed the continued practice of obstetrics, minor surgery, and the prescription of drugs to “reinstate the status quo.” This legislation was vetoed by the governor after the session ended. Also, legislation was passed to fund and commission a study of the education and practices of naturopaths for the use of the 1959 legislative session. The report was devastating in its assessment of the state of naturopathic education in 1959. Essentially, the only school in existence was the National College of Naturopathic Medicine in Portland, Oregon, which at that time was in its early, rudimentary stage. Based on this assessment, no legislative relief was granted to licensed naturopaths in Utah, who were now firmly reduced to practicing without any obstetrics, minor surgery, or prescription rights.200 The 1959 legislature did pass a Basic Science Law. Naturopaths were authorized to take the midwifery examination and become licensed midwives as well as NDs but only after taking the BSL examinations. Also, naturopaths could take the obstetrics and minor surgery examinations as given by the medical board (not their own licensing board) but only after passing the BSL examination (this according to another AG opinion requested by the naturopathic board in 1961). And finally, from yet another 1961 AG opinion, naturopaths were not licensed to do spinal adjustment because by law, naturopaths were separate from chiropractic. From this point, naturopathy in Utah went into a long decline as existing practitioners retired from practice and new practitioners were scarce.201 

Washington State Under Siege In Washington, naturopaths had been in practice under the Washington Drugless Healing Act of 1919 since Robert V. Carroll had founded the Washington State Naturopathic Association in 1934. Before that time, all drugless practitioner licenses listed “Sanipractic,” and practitioners either called themselves “drugless physicians” or “Sanipractors.” Sanipractors used the initials “SP” for Sanipractic Physician. Licenses continued to be issued for “Sanipractic,” but many practitioners demonstrated their alliance with Carroll—and through Carroll’s WSNA, their alliance with the national ANA—by using the initials “ND” in practice. After adverse court decisions in 1947 (drugless healers cannot practice surgery or obstetrics), 1950 (drugless healers are not “doctors” and are not allowed standard malpractice defenses), and 1957 (drugless healers can be prosecuted for practicing medicine without a license for using “Dr.” or “physician,” conducting physical examinations), the Washington naturopaths were completely unsuccessful in getting any legislative relief over the intense opposition of the medical profession. The NDs obtained 53 signatures on a petition submitted to

CHAPTER 4  the Washington licensing department under the Drugless Healing Act and at least gained the right to be licensed to practice “Naturopathy” in Washington. For about 10 years, this obtained a little legal relief for them from some of the bad case law that applied to “Sanipractors.”202 

A Dismal State of Affairs: The 1960s This once proud and vigorous natural healing movement that existed from after WWII for about 10 years had gone into such decline—as described here—that the naturopaths’ self-reported state as of 1968 showed a professional movement almost gone.203 In 1968 consideration was given by the US Department of Health and Human Services to the request by the National Association of Naturopathic Physicians to have naturopaths accepted as independent practitioners under Medicare. As part of this process, a lengthy questionnaire was completed and submitted by John W. Noble, DC, ND. Noble was a 1937 graduate of Western States College of both the School of Chiropractic and the School of Naturopathy. As of 1968, Noble was a licensed ND in Oregon, practicing in Portland. He was NANP president and also maintained the administrative offices of the National College of Naturopathic Medicine, which had recently moved its main instructional facilities to Seattle. As of 1968, he reported that the NANP had 168 members from Washington (26), Idaho (26), Connecticut (24), Oregon (20), California (17), Kansas (16), and New York (7). Of these states, Washington, Idaho, Kansas, and New York were not considered licensed states, so almost half of the NANP membership came from unlicensed jurisdictions.

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Noble reported on behalf of NCNM that from 1960 to 1967, 16 students had graduated, and as of 1967/1968, 7 were enrolled. According to the 1965 US government publication State Licensing of Health Occupations, there were 351 licenses in effect in Arizona, Connecticut, Hawaii, Oregon, Utah, and the District of Columbia—the states still issuing licenses.204 Also, 202 licenses were renewed in Florida and California—states that were not issuing new licenses as of 1965. This was a total of 553 active licenses. Together with identifiable practitioners in the unlicensed states, there may have been 700 or so identifiable naturopaths, some practicing in extremely restrictive circumstances.

A Future Resurrection It would not be until the mid-1970s that this serious decline of natural healing in the United States would begin to be reversed and not until the late 1980s that natural healing would return to an equivalency with the profession that was built between the mid-1930s and the early 1950s by Carroll, Budden, Schlichting, and the others discussed here. That was not, obviously, from lack of commitment or effort on their part.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Lamm, Lester. Oregon Pioneer: The Journey of Chiropractic Education in the Northwest (Portland, OR, University of Western States); Keating, Joseph C., Jr., Callender, Alana K., and Cleveland, Carl S. III (1998) A History of Chiropractic Education in North America (Published by Council on Chiropractic Education, Scottsdale, AZ); 2014. 2. Garceau, O. The Political life of the American Medical Association. (Cambridge, MA: Harvard University Press; Truman), D., (1951). The Governmental Process (New York: Knopf); The American Medical Association: Power, Purpose and Politics in Organized Medicine. (1954) The Yale Law Journal. 1941; 63(7): 937–1022. 3. Berliner H. A System of Scientific Medicine: Philanthropic Foundations in the Flexner Era. New York: Tavistock; 1985. 4. Appleton N. Rethinking Pasteur’s Germ Theory. Berkeley, CA: North Atlantic Books; 2002. 5. Gross CG. Claude Bernard and the constancy of the internal environment. Neuroscientist. 1998;4:380–385. 6. Kirchfeld Boyle. Nature Doctors: Pioneers in Naturopathic Medicine. East Palestine, OH: Buckeye Press; 1994. 7. Lindlahr HMD, Proby CP, eds. Philosophy of Natural Therapeutics. Kent, England: Maidstone Osteopathic Clinic; 1924. Reprint 1975. 8. Ibid, note 5. 9. Ibid, note 6, p. 5. 10. Ibid, note 6, p. 8. 11. Ibid, note 6, pp. 6-7. 12. Ibid, note 6, p. 10. 13. Ibid, note 6, p. 10. 14. Ibid, note 6, pp. 28-35. 15. Keating Jr JC, Rehm WS, William C, Schulze MD. D.C. (1870-1936). From mail-order mechano-therapists to scholarship and professionalism among drugless physicians. Chiropractic Journal of Australia. 1995;25(3):82–92. Sept. 16. Ibid. 17. Ibid. 18. Ibid. 19. Ibid. 20. Ibid. 21. Ibid. Seattle meeting reported in The Seattle Times; 1934. 22. Ibid. 23. Ibid. Dr. Budden and Western States College, with its School of Chiropractic and School of Naturopathy, become part of the story in due course. 24. Cannon WB. The Wisdom of the Body. 2nd ed. New York: W.W. Norton & Co; 1939. 25. Ibid, pp. 240-243. 26. Burrow James G. Organized Medicine in the Progressive Era: The Move Toward Monopoly. Baltimore: Johns Hopkins University Press; 1977. 27. Reed Louis S. The Healing Cults; A Study of Sectarian Medical Practice. Chicago, IL: Univ. of Chicago Press; 1932. 28. See Cody, George (1985) “History of Naturopathic Medicine,” in Textbook of Natural Medicine, Pizzorno and Murray, editors, Seattle, WA, Bastyr College Publications (1993) and New York, Churchill Livingstone (1999). 29. See ibid; also see the extensive work by Susan Cayleff in Cayleff (2016) Nature’s Path: A History of Naturopathic Healing in America, Baltimore, Johns Hopkins University Press, and especially pp. 34-50 and 210-217. 30. Charles. Hazzard. Principles of Osteopathy. Kirksville, MO: self-published. republished Andesite Press; 1899. 31. See Cayleff, Nature’s Path, citing several examples. 32. Lindlahr Henry. Nature Cure; republication by. USA: ReadaClassic.com (2010); 1913:12–14. 33. Ibid, at p. 12. 34. Cayleff, Nature’s Path at pp. 54-55. 35. Bilz, F. E. Natural Method of Healing: A Complete Guide to Health (translated from the latest German edition), Leipzig-London-Paris, F. E. Bilz, publisher, through the International News, Co., New York, in the USA; 1901. 36. Ibid, at p. 7. 37. Lindlahr, Nature Cure, at pp. 17, 20.

38. Evan Willis. Medical Dominance. Sydney, Australia: George Allen & Unwin publishers; 1983. 39. Rosenthal Sau. Lewiston, Maine. Edwin Mellen Pressl; 1986. 40. Berliner H. A System of Scientific Medicine: Philanthropic Foundations in the Flexner Era. New York: Tavistock; 1985. 41. Wolinsky Fredric D. The Sociology of Health: Principles, Professions and Issues. Boston: Little, Brown; 1980:215. 42. Lipset Seymour Martin. American Exceptionalism; A Double-Edged Sword. New York: W.W. Norton; 1996. 43. Cayleff, Nature’s Path at pp. 193, 215. 44. Norman Gevitz. The DOs: Osteopathic Medicine in America. 2nd ed. Baltimore, MD: Johns Hopkins University Press; 2004. 45. Wardwell Walter I. Chiropractic: History and Evolution of a New Profession. St. Louis, MO: Mosby-Elsevier; 1992. 46. Susan Cayleff. Nature’s Path: A History of Naturopathic Healing in America. Baltimore, MD: Johns Hopkins University Press; 2016. 47. Cayleff, Nature’s Path. 48. Kirchfeld Boyle. Nature Doctors: Pioneers in Naturopathic Medicine. East Palestine, OH: Buckeye Press; 1994. 49. Lamm Lester. Oregon Pioneer: The Journey of Chiropractic Education in the Northwest. Portland, OR: University of Western States; 2014:13–14. 50. Ibid. 51. Ibid. 52. Ibid at pp. 14–15. 53. For an extended review of the concept and application of the Basic Science Law see Gevitz Norman. ‘A Coarse Sieve’: Basic Science Boards and Medical Licensure in the United States. Journal of the History of Medicine and Allied Sciences. 1988;43:36–63. 54. For an extended review of the concept and application of the Basic Science Law, see “A Coarse Sieve: Basic Science Boards and Medical Licensure in the United States,” by Norman Gevitz. 55. Budden WA. Medical Propaganda – Aided by B.J. Palmer, Defeats Health Care Amendment. The Chiropractic Journal; 1935. 56. For an extended review of the concept and application of the Basic Science Law, see “A Coarse Sieve: Basic Science Boards and Medical Licensure in the United States,” by Norman Gevitz. 57. Ibid. 58. The Oregonian. 2 Initiative Bills Will Face Voters; 1934. 59. Budden WA. Medical Propaganda – Aided by B.J. Palmer, Defeats Health Care Amendment. The Chiropractic Journal; 1935. 60. Oregon law required expenditure reporting, and $4819.03 was the officially reported expenditure filed by the “yes” campaign. The “no” campaign spent twice as much, with over $6,000 coming from the Oregon Hospital Association. The Oregonian, November 17, 1934; November 18, 1934; November 23, 1934. 61. Lamm, Oregon Pioneer, pp. 25-26. 62. Lamm, Oregon Pioneer. 63. With regard to Sanipractic, its presence in Washington, and its relationship to naturopathy, see Reed, Louis S. The Healing Cults; A Study of Sectarian Medical Practice Chicago, IL, Univ. of Chicago Press; 1932. 64. The Seattle Times, Sunday, April 24, notes a wire story Saturday—the day before—from Washington, D.C., stating that Carroll has been announced to speak before the ANA convention that July. This is the first reported connection of Carroll with the national ANA. 65. Carroll’s original diplomas are in Bastyr University’s John Bastyr archival collections, 66. Kirchfeld and Boyle, Nature Doctors, pp. 257–260, covers the relationship between the Carroll brothers. 67. The records of the Washington State Naturopathic Association including the 1930s are in the John Bastyr Archive collection at Bastyr University as maintained and donated by Kenneth Harmon Freeman, ND. 68. Lust and his publications are discussed in detail in both Cayleff, Nature’s Path, and Kirchfeld and Boyle, Nature Doctors. 69. Schlichting succeeded Robert Carroll as president of the western ANA in 1949; in 1951 the association changed its name to the ANPSA. 70. The Oregonian newspaper, Portland, Oregon, for March 9, 1952 at page 29. 71. Schlichting gave this number in an interview on the first day of the convention (Thursday); the interview appeared in The Oregonian on Friday, March 7, 1952, at p. 45.

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References

72. Licensed states were Connecticut, South Carolina, Georgia, Florida, Texas, Arizona, Utah, and Oregon. Naturopaths were licensed in Washington as drugless healers and in Ohio as “others-mechanotherapy.” 73. The life and career of A.R. Hedges, DC, ND, of Medford, Oregon, will be discussed in a future column. 74. See previous column in IMCJ. 75. Lamm Lester. Oregon Pioneer: The Journey of Chiropractic Education in the Northwest. Portland, OR: University of Western States; 2014:25–26. 76. Ibid at p. 6. 77. Keating Joseph Jr C, Callender Alana K, Cleveland III Carl S. A History of Chiropractic Education in North America. Scottsdale, AZ: Published by Council on Chiropractic Education; 1998:86–87. 78. The Western States College, School of Chiropractic and School of Naturopathy, Schedule of Classes and Hours was obtained from the library archive collection at the University of Western States. 79. The Oregonian newspaper of Portland, Oregon, for Monday, June 28, 1937, had the announcement of the commencement to be held that evening. 80. As quoted in A History of Chiropractic Education in North America, at pp. 85-86. 81. As noted in the author’s personal correspondence with Gerald Farnsworth, DC, ND, of British Columbia, Canada (June 2015). He was a personal and professional friend and colleague of Joseph Boucher, ND, WSC class of 1953, and the brother of Earl Farnsworth, ND, class of 1955. 82. The Oregonian, Monday, June 11, 1934, reports on the meeting from the week before, noting that Harold Hulme of the campaign was reelected secretary-treasurer, that Dr. Budden had passed out diplomas for the postgraduate course as well as speaking on “The Dawn of Medical Freedom,” and that Dr. Benedict Lust of New York was the principal banquet speaker. 83. A lot of the story up to 1943 is told—from Dr. Lust’s point of view—in the Naturopath and Herald of Health (NHH) volumes for July 1942, “Dr. Lust Speaking,” and January 1943, “The American Naturopathic Association Its Purposes and Objectives.” Any other volumes of NHH and any other sources will be noted. 84. The constitution and bylaws adopted in 1935 were printed and published in Naturopath and Herald of Health, November 1935 and January 1936. 85. Naturopath and Herald of Health, November, 1941; January, 1942. 86. Naturopath and Herald of Health, July, 1942; August, 1942; January, 1943; Newsletter from the American Naturopathic Association, Office of the Secretary, Midland, Texas, dated March 1, 1947, listing Robert A. Carroll as President; American Naturopath, Volume III, No. 4, June 1947; Herald of Health and Naturopath, October, 1947; November, 1947 (Published by T.J. Schippell, Wash., D.C.) in the editor’s column, “This Month with Dr. Schippell,” all have been parsed through to gather this history. This material is in the collected archives at the National University of Natural Health, Portland, Oregon. 87. Ibid. 88. Herald of Health and Naturopath, September, 1947 (Vol. 52, No. 9). Following Dr. Lust’s death in 1945 Dr. Schippell took over publication of this publication in the name of the (eastern) ANA, each monthly cover noting: “Founded in 1896 by Benedict Lust, Father of Naturopathy,” with the main editorials being “This Month with Dr. T.M. Schippell” and “Dr. Lust Speaking (reprints).” 89. “Outline of Curriculum for Schools and Colleges Teaching Naturopathy” by the ANA Committee on Education and Council on Schools and Colleges, adopted by the ANA House of delegates at the Annual meeting July, 1948 at Salt Lake City, and reported in Journal of the ANA, Inc., December-January, 1948-1949, pp. 11,21. 90. The first visit is reported in The Oregonian, Friday, December 3, 1947, and the second visit is reported in the Journal of the ANA, February, 1949, at p. 13; “National News Notes” report on the ONA’s convention in December 1948, also attended by a student delegation from Western States of 23 students, and further, in the Newsletter of the Washington State Naturopathic Association for February 1948, a copy of which is the John Bastyr Archive papers at Bastyr University. 91. Kelly v. O.G. Carroll, 36 Wn.2d 482, 219 P.2d 79 (1950). 92. Journal of the ANA, vol. 4, no. 6, June,1951, at p. 8 has an “In Memoriam” box noting Carroll’s passing on Friday, May 11, 1951; Obituary in Seattle Times, Sunday, May 13, 1951.

93. The primary tools for this analysis are the catalogs for the programs at WSC maintained in the UWS library archives and the textbooks referred to in these catalogs. The catalogs available will be referenced as the curriculum for each period is discussed. 94. Reference is to the catalogs in use in 1934–1937 and 1938–1939; UWS library archives. 95. UWS library archives. 96. Ibid. 97. Lake’s Treatment is described by Susan Cayleff at p. 38 of Nature’s Path: Naturopathic Healing in America (2016), Baltimore, Johns Hopkins Press, as presenting osteopathy, chiropractic, and naturopathy as a complementary set of skills necessary to a complete physician. 98. UWS library archives. 99. H. Riley Spitler, DC, ND, OD, of Eaton, Ohio was a pre-WWI graduate of Ross Chiropractic College of Fort Wayne, Indiana. Spitler was truly a renaissance man who deserves his own biography, and later in this series, he will get one. Among other things, he was a medical board examiner in neuropathy in Ohio for over 15 years; a member of the faculty of the Metropolitan Chiropractic College of Cleveland, Ohio, in mechanotherapy; and the originator of the syntonic principle that is still influential in optometry today. 100. UWS library archives. 101. The reference is to Rehm and Keating, as discussed previously. See IMCJ for February 2018, vol. 17, no. 1 at p. 20 102. Medford (OR) Mail-Tribune, Tuesday, June 10, 1930—front-page story reporting the newest census figures. 103. Medford (OR) Mail-Tribune, Sunday, April 4, 1943, references Hedges’s 32 years in practice in Medford and observing an annual “Health Week”; Wednesday, February 28, 1962, notes Hedges as receiving only the fourth “Lifetime Membership” in the Oregon Association of Chiropractic Physicians, having been in practice in Medford since 1911; the first of many regular ads for the Hedges practice that has been located in newspaper archives is in the edition for Wednesday, April 9, 1913. 104. Medford (OR) Mail-Tribune, Tuesday, March 4, 1930. 105. Ibid. 106. Lamm Lester. Oregon Pioneer: The Journey of Chiropractic Education in the Northwest. Portland, OR: University of Western States; 2014:22. 107. Amarillo Globe-Times, Tuesday, July 15, 1941. 108. Oakland Tribune, Thursday, December 18, 1941. 109. The Oregonian, Sunday, July 26, 1942, reported the election as VP; Friday, January 1, 1943, reported the Board appointment. 110. The Sunday, June 3, 1934, edition of The Oregonian had reported on the 25th Annual Meeting of the ONA, at which Budden spoke on the Ballot Campaign, and Hedges and Sargent and others participated in “a clinic demonstrating naturopathic procedures.” 111. (Salem) Statesman-Journal, Sunday, June 30, 1946; term effective July 2. 112. Medford Mail Tribune, Tuesday, November 29, 1949. 113. See “Editorial’ in Journal of the American Naturopathic Association, vol. 3, no. 11, November, 1950. 114. See “Editorial”. Journal of the American Naturopathic Association. June 1950;3(5). May 1950; see also “Editorial” in vol. 3, no. 6,. 115. Sunday, March 7, 1954, The Oregonian—meeting announcement for Friday, March 12, 1954. 116. Altschuler Glenn C, Blumin Stuart M. The GI Bill: A New Deal for Veterans. New York: Oxford Univ Press; 2009. 117. Oregon Pioneer, at p. 23. 118. A.E. Homewood at p. 30. 119. Martin Bleything’s background is discussed at length in a newspaper profile when he also graduated from Portland’s Lewis and Clark University with a BA in journalism in 1955—at age 65. The information about Grace University comes from materials in the John Bastyr Archives at Bastyr University. 120. Journal of the ANA, vol. 4, no. 6, June 1951. 121. There is a great deal of academic scholarship about these events, most extensively in Monte Poen’s Harry S. Truman Versus the Medical Lobby: The Genesis of Medicare (1979), Columbia, MO, University of Missouri Press. For capsule glimpses of the political power of the AMA, see Truman, David B. (1951; 2nd ed. 1971), New York, Alfred Knopf Publishing,

References pp. 170–177, 231–232. For the AMA battle with President Truman, see Hacker, Jacob S. (2002) The Divided Welfare State: The Battle over Public and Private Social Benefits in the United States, New York, Cambridge University Press, pp. 222–237. For a discussion of how these issues relate to the elements of medical dominance in U.S. healthcare policy, see Morone, James A. (1990; rev. ed. 1998), The Democratic Wish: Popular Participation and the Limits of American Government, revised edition New Haven, CT, Yale University Press 122. The AMA campaign that began in 1953 will be discussed more extensively later in the chapter. 123. Lamm Lester. Oregon Pioneer: The Journey of Chiropractic Education in the Northwest. Portland, OR: University of Western States; 2014. 124. This curriculum information comes from archived the college catalogs, officially called “Bulletin of the Western States College.” These are archived in the library collection in the W. A. Budden Library at the University of Western States. For this section, these Bulletins have been referenced: Volume No. XXV, June 1949, Annual Catalog Schools of Chiropractic and Naturopathy for 1949–1950; Volume No. XXVI, June 1950; Annual Catalog Schools of Chiropractic and Naturopathy for 1950–1951; Volume No. XXVII, March 1951, Annual Catalog Schools of Chiropractic and Naturopathy for 1951–1952; No. XXVII (2), March 1951; Annual Catalog School of Naturopathy for 1951–1952; No. XXVIII, May 1952, Annual Catalog Schools of Chiropractic and Naturopathy for 1952–1953. 125. The Synergist was the monthly “Voice of the Student Body” of the time. As vol. 4, no. 7 was April 1953 as the class of 1953 was graduating, this monthly looks like publication was begun as the class arrived in fall 1949. These sketches of campus life come from the several volumes archived at UWS. 126. See previous references to Dr. Schlichting’s speeches on the state of naturopathy, circa 1952. 127. The Oregonian, Saturday, March 7, 1953. 128. The Oregonian, Wednesday, March 11, 1953. 129. The convention news itself was in The Oregonian, Friday, July 17, 1953, with lengthy interview coverage of the convention appearance by soils and food sciences professor from the University of Missouri, Dr. William Albracht. 130. Ibid. 131. An obituary in The Oregonian, Wednesday, August 18, 1954, notes his death on August 1. The circumstances are described in Oregon Pioneer, at p. 27. 132. Oregon Pioneer, pp. 33-34. 133. Nature Doctors, by Kirchfeld and Boyle at pp. 297–302 covers the career in naturopathy of Joe Boucher. 134. Oregon Pioneer, see especially 104–105. 135. Nature Doctors p. 310; more discussion of this later in the chapter. 136. Ibid. 137. Journal of the ANPSA, September, 1952 (volume 6, number 6). 138. The National Chiropractic Journal, September, 1939 (Vol. 8, No. 9). 139. El Paso Herald-Post, Monday, April 8, 1957; Amarillo Globe-Times (TX), Monday, May 09, 1938; Amarillo Sunday News and Globe, Sunday, August 14, 1938; Midland Reporter-Telegram, Wednesday, November 26, 1941 and Monday, November 24, 1941 and Monday, January 12, 1942. 140. Various issues of the Midland Reporter-Telegram from 1941–1944 carried ads for Dr. Schlichting’s practice “emphasizing fractures and dislocations”; the Carver technique is discussed in Wardwell, Walter (1992) Chiropractic: History and Evolution of a New Profession (St. Louis, Mosby, Inc.). 141. Midland Reporter-Telegram, Monday, November 24, 1941. 142. See previous column re: ANA convention of 1942 and The Canyon (TX) News, Thursday, November 2 and Thursday, November 9, 1944, and Thursday, October 25, 1945 re: H. A. Brown, ND. 143. See Note 132. 144. Walter Wardwell. Chiropractic: History and Evolution of a New Profession. St. Louis: Mosby, Inc; 1992. 145. Ibid, p. 89. 146. Johnson, Alton Cornelius (1939), Principles and Practice of Drugless Therapeutics (Los Angeles, Chiropractic Educational Extension Bureau); see previous column on Western States’ postwar curriculum; see Journal of the ANA and ANPSA 1948–1954, especially Journal of the ANA September 1948 (vol. 1, no. 9) at page 18 for Johnson’s initial column on physiotherapy and his explanation of being recruited for and acceptance of his position.

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147. See previous columns and specifically: Naturopath and Herald of Health, July 1942; August 1942; January 1943; Newsletter from the American Naturopathic Association, Office of the Secretary, Midland, Texas, dated March 1, 1947, listing Robert A. Carroll as president; American Naturopath, vo. III, no. 4, June 1947; Herald of Health and Naturopath, October, 1947; November, 1947 (Published by T. J. Schippell, Washington, D.C.) in the editor’s column, “This Month with Dr. Schippell”; all have been parsed through to gather this history. This material is in the collected archives at the National University of Natural Health, Portland, Oregon. 148. Ibid. The constitution and bylaws adopted in 1935 were printed and published in Naturopath and Herald of Health, November 1935 and January 1936; Naturopath and Herald of Health, November 1941; January 1942. 149. See also Journal of the ANA, April 1948 (vol. 1, no. 4); August 1948 (vol. 1, no. 8); and September 1948 (vol. 1, no. 9). 150. Wardwell Walter. Chiropractic: History and Evolution of a New Profession. St. Louis: Mosby, Inc; 1992; Keating Joseph C Jr, Callender Alana K, Cleveland Carl S III. A History of Chiropractic Education in North America. Scottsdale, AZ: Council on Chiropractic Education; 1998. 151. Fort Wayne (IN) News and Sentinel, July 23, 1918; Keating et al. (note xiii); John Bastyr’s diploma and other information are in archives or on display at Bastyr University; for the story of mixers licensed as NDs in “straight” states such as Utah and South Carolina, see Phillips, Reed B. (2006) Joseph Janse: The Apostle of Chiropractic Education (Reed Phillips, publisher). 152. See El Paso Herald-Post, Monday, April 8, 1957. 153. Journal of the ANA July, 1949 (vol. 2, no. 7). 154. Journal of the ANA July, 1949 (vol. 2, no. 7). 155. Keating Joseph Jr C, Callender Alana K, Cleveland Carl III S. A History of Chiropractic Education in North America (Scottsdale, AZ. Council on Chiropractic Education; 1998. 156. Journal of the ANA June, 1951 (Vol. 4, No.6)—W. Martin Bleything, Editor. 157. Journal of the ANA June, 1951 (Vol. 4, No.6)—W. Martin Bleything, Editor. 158. Journal of the ANA June, 1951 (Vol. 4, No.6); Reno Evening Gazette, March 6, 7, 15, 1951; The Atlanta Constitution, February, 17, 1950; Keating, Joseph C., Jr., Callender, Alana K., and Cleveland, Carl S. III (1998) A History of Chiropractic Education in North America, (Scottsdale, AZ, Council on Chiropractic Education). 159. Attorney general’s Opinion Letter V-1486, July 29, 1952, to Henry J. Schlichting, ND, Secretary, Texas Board of Naturopathic Examiners; Journal of the ANA, September 1948, for Dr. Spitler’s remarks on Tennessee. 160. The Connecticut story told here is taken from coverage by The Hartford Courant for the following dates: June 6, August 20, 1946; March 20, April 24, May 7 and 29, July 16, 1947; and January 22 and 23, 1948. 161. The South Carolina story is taken from the coverage of the Charleston (SC) News and Courier for June 27, 1946; April 24, May 14 and 28, November 15, 1947; and April 11, 1949. 162. AG Opinion Letter V-1486, July 29, 1952, to Henry J. Schlichting, ND, Secretary, Texas Board of Naturopathic Examiners. 163. Journal of the ANA August, 1951; Journal of the ANPSA October and November, 1951. 164. Journal of ANPSA, September, 1951. 165. Proceedings of the House of Delegates. American Medical Association Annual Meeting; 1953. 166. Poen Monte M, Harry S. Truman Versus the Medical Lobby. Columbia, MO, Preface: University of Missouri Press; 1979. 167. (2013) (The Johns Hopkins University Press, Baltimore). 168. Volume 71, Issue 3, July 1, 2016. 169. AG Opinion Letter V-1486, July 29, 1952, to Henry J. Schlichting, ND, Secretary, Texas Board of Naturopathic Examiners. 170. See AG Opinion Letter S-60, to Austin F. Anderson, Criminal District Attorney, June 29, 1953, “Re: Constitutionality of Article 4590d, V.C.S. relating to the practice of naturopathy.” 171. See Sabota, Leo M. and Martin, J. David “The Texas Attorney General-An Alternate State Supreme Court,” in Kraemer, Carin and Maxwell (1975) Understanding Texas Politics (West Publishing Co., St. Paul, MN). 172. Committee Report to 1948 Convention of the ANA, Salt Lake City, UT, June, 1948, as reported in Journal of the ANA for September, 1948.

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References

173. Kuts-Cheraux AW. Naturae Medicina and Naturopathic Dispensatory. American Naturopathic Physicians & Surgeons Assn., Des Moines, IA. Chattanooga, TN: Lulu Enterprises, Inc; 1953. Reprint (2007). 174. Altschuler Glenn C, Blumin Stuart M. The GI Bill: A New Deal for Veterans. New York: Oxford Univ. Press; 2009. 175. Keating Joseph Jr C, Callender Alana K, Cleveland Carl III S. A History of Chiropractic Education in North America. Scottsdale, AZ: Published by Council on Chiropractic Education; 1998. 176. Commencement announcement—UWS Archives. 177. See Pittsburgh Press, Sunday, June 27, 1954, for extensive coverage of the Hoxsey cancer treatment events in Pennsylvania in the summer of 1954. Hoxsey had been battling the U.S. government since 1950 in Texas, but it was only in 1953 and 1954 that he began being described as a “naturopath.” See Dallas Morning News, Tuesday, June 30, 1953; for more on Hoxsey’s entire career, which began in his native Iowa in the 1930s, see The Los Angeles Times, September 29, 1988, review of the documentary Hoxsey: Quacks Who Cure Cancer. 178. Abilene Reporter-News, February 8, 1955; The Cameron (TX) Herald, February 17, 1955; The Corpus Christi (TX) Caller-Times, February 3, 1955. 179. The history of WSC after Dr. Budden’s death through the discontinuance of the School of Naturopathy is taken from Oregon Pioneer, pp. 31–35; A History of Chiropractic Education in North America, pp. 361–372, especially; and correspondence between Dr. Ralph Failor and Dr. Higgens and associated records from Dr. Failor’s tenure found in the UWS library archives. 180. The Austin (TX) American, January 25, 1956; March 28, 1956; Austin (TX) American-Statesman, May 25, 1956. 181. There were over 1000 news stories statewide in Texas in 1957 reporting the Texas naturopaths’ saga. This telling here draws from all of them, but specifically from the coverage by The Austin (TX) American for these dates: February 27, March 1, 4, 5, 8, 10, 13, 17, 19, 24, 28, April 3, 8, 12, 21, 24, May 2, 3, 8, 9, 10, 15, 23, 31, July 1, 7, 9, 13, 15, 25, 26, August 1, October 6, 8, 11, 12, 14, 21; and the Austin (TX) American-Statesman for February 28, March 4, 7, 12, 15, 20, 28, April 1, 3, 19, 27, May 6, 8, 31, July 1, 3, 8, 13, 25, October 2, 16. Also The Odessa (TX) American for April 19, 1957, about the “mystery witness.” 182. Valley Morning Star (Harlingen, TX), January 31, 1957 (Associated Press).

183. El Paso Herald-Post May 1 and May 3, 1957; C.I. Douglas, Reporter. 184. Ibid. 185. Austin American December 3, 9, 23, 24, 29; Austin American-Statesman 12/ 2. 186. Ibid. 187. Austin American January, 23, February 20, March 26; Austin American-Statesman February 19, 1958. 188. Big Spring Herald (TX) January 22, 1961; Midland Reporter-Telegram (TX) April 30, 1962; Arizona Republic September 7, 1965; Arizona Republic, June 5, 1973; Lubbock Avalanche-Journal, June 6, 1973. 189. The Miami Herald April 19, April 20, 1949. 190. The State, Columbia, SC, March 17, 1955. 191. The Miami Herald April 19, 20, 1949. 192. The Miami Herald, April 20, 1949. 193. Lawrence Thompson, Reporter, The Miami Herald. 194. Charleston News and Courier, May 1, 1955. 195. Miami Daily News, Jane wood, Reporter, November 23, 24, December 1, 2, 1955 196. Miami Daily News, April 4, 1957. 197. Salt Lake Telegram, March 24, 1925; Salt City Telegram, March 5, 1937; The Salt Lake Tribune, February 16, 1939; Salt Lake Telegram, legislative coverage February of each legislative session, 1941, 1943, 1945. 198. Salt Lake Tribune, September 20, 1946. 199. The Ogden (UT) Standard-Examiner, September 3, 1955. 200. The Daily Herald (Provo, Utah), June 19, 1956; August 9, 1956; December 21, 1956. 201. The Ogden Standard-Examiner (Ogden, UT), March 22, 1957. 202. Salt Lake City Tribune, January 29, 1959; The Ogden Standard-Examiner (Ogden, UT), March 25, 1959; The Salt Lake Tribune, November 2, 1961. 203. State v. Houck, 32 Wn. (2d) 681,203 P. (2d) 693 (1949); Kelly v. Carroll, 36 Wn.2d 482, 219 P.2d 79 (1950); State v. Kelsey, 46 Wn.2d 617, 283 P.2d 982 (1955). 204. Independent Practitioners Under Medicare: A Report to the Congress. U.S. Department of Health, Education and Welfare, William J. Cohen, Secretary, Naturopathy; 1968:126–145. 205. Ibid at page 137.

5 Philosophy of Naturopathic Medicine Rachelle S. Bradley, ND

OUTLINE Introduction, 80 Medical Philosophy, 80 Vitalism Versus Mechanism, 80 Vitalism, 81 Meaning of Disease, 83 Scientific Medicine, 84

INTRODUCTION This chapter examines the philosophical foundation of naturopathic medicine and its modern applications. Unlike most other health care systems, naturopathy is not identified by any particular therapy or modalities (e.g., conventional medicine, drugs and surgery; chiropractic, spinal manipulation). A wide variety of therapeutic styles and modalities are found within the naturopathic community (Box 5.1). For example, there are still practitioners who adhere to the strict “nature cure” tradition and focus only on diet, “detoxification,” lifestyle modification, and hydrotherapy. There are also those who specialize in homeopathy, acupuncture, or natural childbirth. At the other end of the spectrum are naturopathic physicians who use botanical medicines, nutraceuticals, and pharmacology extensively to manipulate the body’s biochemistry and physiology. Finally, there is the majority, who practice an eclectic naturopathic practice that includes a little of everything. Since its inception 130 years ago, naturopathic medicine has been an eclectic system of health care. This characteristic has allowed it to adopt many of the more effective elements of natural and alternative medicine and to adopt conventional medicine’s basic and clinical sciences, diagnostics, and pharmacology. Through all of this eclecticism, naturopathic medicine has always identified the Latin expression vis medicatrix naturae (the healing power of nature) as its philosophical linchpin. However, the expression vis medicatrix naturae, by itself, does not provide a clear picture of naturopathic medical philosophy or an understanding of the practice of naturopathic medicine in all of its varied forms. With the profession’s history of eclecticism, no two practitioners treat any individual patient exactly alike. This situation has its advantages (e.g., individualization of each patient’s care, more therapeutic options) but also makes it difficult to perceive the profession’s philosophical cohesiveness. Another major disadvantage of this eclecticism is the difficulty in developing consistent practice standards. To attempt to solve this problem, the modern profession has articulated a general statement of naturopathic principles that expand on

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Naturopathic Philosophy, 84 Vis Medicatrix Naturae, 84 Natural Medicines and Therapies, 85 Family and Specialty Practice, 85 The Philosophical Continuum, 86 Conclusion, 86

vis medicatrix naturae (Box 5.2). However, to gain a more in-depth understanding of naturopathic medicine, one must discuss medical philosophy in general. 

MEDICAL PHILOSOPHY The issues fundamental to a discussion of medical philosophy have changed little since naturopathy first appeared as a distinct profession at the end of the 19th century. What has changed is the level of understanding of the biological process and the language of science. Most people who study the early writers on naturopathic medical philosophy quickly get lost in the archaic language and arguments used to justify the theories. This chapter translates these concepts and issues into modern terms.

Vitalism Versus Mechanism Historically, there have been two main medical philosophies, those of vitalism and mechanism. Their origins can be traced to the Hippocratic writings of ancient Greece. Throughout history, the line separating these two schools of thought has not always been clear, but their philosophical perspectives have generally been in opposition. The conflicting goals and philosophical foundations of these two concepts remain relevant as the modern practices of conventional and alternative physicians come into conflict. As will be seen, the foundations of naturopathic medical philosophy are found in vitalism. However, naturopathy also recognizes the practical value of the mechanistic approach to health care.

Mechanism Up to the early part of the 20th century, there was considerable debate over the issue of vitalism versus mechanism in the field of biology. The mechanists, or materialists, maintained that the phenomenon of life could be explained exclusively as the product of a complex series of chemical and physical reactions. They denied the possibility that the animate had any special quality that distinguished it from the

CHAPTER 5 

BOX 5.1  Naturopathic Modalities Naturopathic physicians are trained to use a number of diagnostic and treatment techniques. These modalities include the following: • Diagnosis. All the conventional clinical laboratory, physical diagnosis, and imaging (e.g., radiography) techniques, as well as holistic evaluation techniques • Counseling. Lifestyle, nutritional, and psychological • Natural medicines. Nutraceuticals (i.e., all food constituents, constituents of biochemical pathways, etc.), botanical medicine, and homeopathy • Physical medicine. Hydrotherapy, naturopathic manipulative therapy, physiotherapy modalities, exercise therapy, and acupuncture • Family practice. Natural childbirth, minor surgery, natural hormones, biologicals, and pharmaceuticals

BOX 5.2  The Principles of Naturopathic

Medicine

The Healing Power of Nature: Vis Medicatrix Naturae Nature acts powerfully through healing mechanisms in the body and mind to maintain and restore health. Naturopathic physicians work to restore and support these inherent healing systems when they have broken down by using methods, medicines, and techniques that are in harmony with natural processes.  First Do No Harm: Primum Non Nocere Naturopathic physicians prefer noninvasive treatments that minimize the risks of harmful side effects. They are trained to know which patients they can treat safely and which ones they must refer to other health care practitioners.  Find the Cause: Tolle Causam Every illness has an underlying cause, often in aspects of the lifestyle, diet, or habits of the individual. A naturopathic physician is trained to find and remove the underlying cause of a disease.  Doctor as Teacher: Docere A principal objective of naturopathic medicine is to educate the patient and emphasize self-responsibility for health. Naturopathic physicians also recognize and employ the therapeutic potential of the doctor–patient relationship.  Treat the Whole Person Health or disease comes from a complex interaction of physical, emotional, dietary, genetic, environmental, lifestyle, and other factors. Naturopathic physicians treat the whole person, taking all of these factors into account.  Preventive Medicine The naturopathic approach to health care can prevent minor illnesses from developing into more serious or chronic degenerative diseases. Patients are taught the principles with which to live a healthy life; by following these principles they can prevent major illnesses.

inanimate. It was their contention that the only difference between life and nonlife was the degree of complexity of the system. Mechanism has several other distinctive characteristics. Its most obvious is that it is reductionistic. Reductionism is often used as a synonym for mechanism. Mechanistic science is also characterized by an emphasis on linear causality. Without this emphasis on reductionism and linear causality, Western science and medicine would probably have not been so successful. As the 20th century advanced, each new discovery in biological and medical science reinforced the arguments for mechanism, until, by the middle of the century, the biology community had almost exclusively embraced the philosophy of mechanism.

Philosophy of Naturopathic Medicine

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Mechanism is the philosophical foundation of biomedical science and conventional medicine. It is especially visible in the treatment modalities of surgery and most pharmaceuticals. Mechanistic medicine identifies disease and its accompanying signs and symptoms as simply the result of a disruption of normal chemical reactions and physical activities. Such disruptions are caused by the direct interference in these reactions and activities of a “pathogenic agent.” (For the purposes of this discussion, the expression “pathogenic agent” refers to any known or unknown etiological agent, influence, or condition; examples are microbial agents, autotoxins, genetic defects, environmental toxins, non–end-product metabolites, and physical and emotional stress and trauma.) A living organism, then, is simply a very complex machine that, as a result of external agents and influences and “wear and tear,” breaks down. Because the signs and symptoms of disease are thought to be caused only by these mechanical disruptions and interference with reactions, they are considered to be completely destructive phenomena and are therefore to be eliminated. Disappearance of the signs and symptoms indicates that the pathogenic agent and its resulting disease have been eradicated or, more likely, controlled. The goals of mechanistic medicine tend to be the quick removal of the signs, symptoms, and pathogenic agent. Mechanistic medicine is being practiced in cases in which the intention of the therapy is to intervene in the perceived mechanism of the disease and/or to relieve the symptoms. Examples would be the use of antihistamines to relieve rhinitis, vitamin B6 to help carpal tunnel syndrome, emergency care for traumatic injuries, coronary bypass surgery for blocked arteries, and insulin in juvenile-onset diabetes. Mechanism is also being used when an identified pathogenic agent is directly attacked or eliminated; for example, the use of antibiotics or the isolation of a patient from a particular allergen. Clearly, mechanistic medicine can be very effective in achieving its goals. In the presence of modern medical technology, it is easy to see how this philosophy came to dominate biology, medicine, and the attention of the public. However, the unsolved problems of mechanistic medicine—particularly those of chronic degenerative disease; authoritarianism, which alienates patients from responsibility for their own health; and the rising cost of health care—suggest that there are limits to the mechanistic perspective and explain why vitalism has not disappeared and is in resurgence. 

Vitalism The philosophy of vitalism is based on the concept that life is too well organized to be explained simply as a complex assemblage of chemical and physical reactions (i.e., a living system is more than just the sum of its parts). This is in contrast to the mechanist’s contention that “the only difference between life and non-life is the degree of complexity.” Throughout the 19th century, the debate between vitalism and mechanism was carried out mostly by biologists and, in medicine, between the “regular” doctors and those doctors who would now be called alternative. In the medicine of the 19th and early 20th centuries these would have been homeopathic, hydrotherapy, nature cure, and eclectic doctors—all medical doctors with equivalent credentials under the laws of the time. Although the specific terms of “vitalism” and “mechanism” were not necessarily the nomenclature of their debate, the perspectives were the same. Interestingly, through most of the 19th century this debate within the medical community was distinctively not based on science as we currently think of it. The “regular” doctors of the era, as represented by the American Medical Association, were still strongly influenced by Galen’s theory of disease of the four humors with its imaginary anatomy and physiology, bleeding, leeches, mercury, and other horrific treatments. Both the homeopaths and eclectic doctors argued based on

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Philosophy of Natural Medicine

empirical evidence; on the other side, the regular doctors argued based on a dogmatic theory that was more than 1500 years old and unsupported by any evidence. Harris Coulter produced the seminal work on this debate in his three-volume book, The Divided Legacy. The debate between vitalism and mechanism within the field of biology is well documented within the biology journals of the time. This was an era of amazing discoveries about how life functioned. Naturally, this is where the focus of this debate took place for biologists. As the secrets of cellular metabolism were revealed, this debate lurched from one specific argument to the next. The issue was where in the living organism did “God” have direct control. For example, at one point it was argued that the “seat of the soul” was the cell. As the cell was better understood, the place that was the point of God’s intervention was postulated to be the nucleus. As research further revealed how the organelles functioned, the vitalistic biologists gave up ground until vitalism as a distinct philosophy in biology was finally abandoned. The error that doomed the vitalistic-oriented biologists was that they were all reductionistic in the same way as the mechanistic biologists. Reductionistic science seems completely able to learn how life functions from a biochemical and biophysical perspective. Eventually, all of the individual chemical and physical reactions that are found in the processes of life will probably be identified. However, the vitalistic biologists missed the most essential aspect of vitalism: holism. In naturopathy’s early years there were few interactions between it and the academic and research worlds. The great authors and practitioners came to naturopathy through “conversion,” in other words, most had been cured of some health problem by a natural cure and felt naturopathy and curing the sick was now their calling. There is no evidence that these naturopaths even knew that this debate between vitalism and mechanism was going on in the biology literature. Research in this early era of naturopathy consisted of observing nature and applying these observations to treating patients. This led to a deep appreciation of “nature’s” desire for balance and order (what a physiologist would call homeostasis). This holistic perspective, combined with the results of the naturopathic treatments, was the empirical evidence that drove their understanding of health and disease. It was only in the latter half of the 20th century that the field of naturopathic medicine began to converge with the academic and research worlds. Since the 1970s this convergence has moved at breakneck speed, until today there is no longer any real distinction (although this is not evident in some of the politically motivated diatribes against the field of natural medicine). However, by this time the academic and research worlds had long since forgotten about vitalism. An organism’s unique complexity—as demonstrated by its ability to grow and develop, respond to stimuli, reproduce, and repair itself—requires a level of organization and coordination that suggests a distinct quality that is not readily explained by mechanism. This is studied extensively by all medical students in physiology class as the “normal” homeostatic process common to all living organisms. However, the tendency in conventional medical school is to put the concept aside when the student moves on to study pathology and the clinical sciences. Yet up to the point of death, maintaining homeostasis is a prime, if not the primary, driving force in all living organisms. To think that homeostasis is only an important factor in “normal” physiological processes and has no relevance in pathology is to ignore all of the basic sciences. All life is attempting to return to this ideal state whenever injured or ill. The only point in the life cycle that an organism is no longer “trying” to maintain homeostasis is death. Reductionistic science has done a wonderful job elucidating the functions of the various components of life, but it tends to focus the researcher and the physician on the disease process as an isolated phenomenon rather than the result of a complex reaction of the whole

organism to a pathological agent. Fortunately, the debate between the vitalistic and mechanistic perspectives in the modern era focuses on the more relevant and holistic general concepts. Although modern vitalism is inherently holistic in its view, there is no conflict with the findings of biomedical science. What is significant is not the individual biochemical or biophysical reactions, but the fact that they are all coordinated to such a degree as to produce the special activities of a living organism. Because there is no inanimate counterpart to this level of complexity and organization, homeostasis is the most dramatic general argument in favor of vitalism. A less dramatic argument supporting the vitalistic perspective is the “problem of entropy.” Entropy is the tendency of any closed system to find equilibrium, that is, the state of least organization. In other words, systems tend to run down and become less complex over time. In defiance of this universal rule, life, up until the point of death, consistently creates more complex systems out of simple ones. To do this, life actively pursues external matter and energy to incorporate into itself while also selectively eliminating byproducts from its use of this matter and energy. When the problem of entropy is examined on the molecular level, the same individual chemical processes and elements may be found in both animate and inanimate systems. In the inanimate system, however, there is a constant move toward a state of chemical equilibrium. This type of system cannot maintain an unstable chemical state and always seeks stabilization. Even after the addition of external exciting energy, the system returns to the simplest, least reactive state possible. The animate system is virtually the opposite. It is continuously in a state of dynamic chemical instability, actively seeking energy to maintain this instability and consistently moving to more complex and more organized states (and back again). It is only at the onset of death that an animate system begins to move toward equilibrium, and, of course, then it is no longer animate. The third general argument in favor of a vitalistic view of life is evolution. For evolution to exist as a force in nature, generations of living organisms have to survive long enough to grow, reproduce, and then evolve. For this survival to take place, the organisms’ homeostatic and repair processes must be consistently directed toward maintaining a state of balance with the external environment (i.e., health). Any organism that does not behave biochemically and physiologically in this manner dies and cannot evolve. Thus the phenomenon of evolution, as the action of countless living organisms over eons, multiplies life’s antientropic quality and is incompatible with a mechanistic view of living systems. These easily observable examples of life’s “special quality” suggest an “organizing force” that goes beyond what is possible from mere chemistry. This quality that makes life unique should not be mistaken as a metaphysical concept, although an argument for or against such concepts is not intended here. The point is only that vitalism is a medical philosophy based on observable scientific phenomena. Unfortunately, a definitive definition of this quality (in the old literature called the “vital force,” defense mechanism, or simply “Nature”) will have to wait for vitalistically or holistically oriented researchers. Reductionistic research has not provided much clarification of these special qualities of life—just ask a modern reductionistic biologist to explain how homeostasis works. They can describe what happens on a biochemical and biophysical level, but they cannot describe why it happens. At this point in the discussion, not many mechanistic practitioners would have reason to be uncomfortable. However, the conflict becomes evident with examination of the premises on which the practice of vitalistic medicine is based. What truly separates vitalism from mechanism and makes it useful as a medical philosophy is its perspective on disease and its associated symptoms. 

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BOX 5.3  Cure, Suppression, Palliation, and Healing Cure: A cure occurs when: (a) a treatment is given to the person; (b) the signs and symptoms of the disease go away; (c) the treatment is removed and the signs and symptoms stay away; and (d) the whole person is healthier and less likely to get sick than before the illness. This is almost always going to occur only when the whole person was treated, and not just the disease or its symptoms. Palliation and suppression never lead to cure in and of themselves. Palliation: Palliation occurs when: (a) a treatment is given for the disease; (b) the signs and symptoms of the disease go away; but (c) when the treatment is removed the signs and symptoms return. The symptoms of the disease are simply being controlled (not cured) as long as the treatment is continued. It is a classic error of many practitioners and patients to equate palliation with moving toward cure. Palliation is on the opposite end of the spectrum as cure and is closer to suppression. Palliation can be useful but, in and of itself, never leads to cure—other more vitalistic and holistic interventions are necessary and may be as simple as changing to a healthier diet, removing some obstacle to recovery, or reducing stress, or as complex as classical homeopathy or traditional Chinese medicine. When palliation is used over a long enough time, suppression is the natural consequence. Palliation is the most common result of almost all health care interventions. This is especially true of conventional medicine but also true for much of alternative medicine as well. Unfortunately, both the practitioner and the patient’s expectations are frequently satisfied with palliation. This is the most frustrating aspect of modern health care, whether conventional or alternative. Too few people are striving for a cure.

Meaning of Disease Vitalism maintains that the pathogenic agent does not directly cause most symptoms accompanying disease; rather, they are the result of the organism’s intrinsic response or reaction to the agent and the organism’s attempt to defend and heal itself. Symptoms, then, are part of a constructive phenomenon that is the best “choice” the organism can make, given the circumstances at any particular time. Symptoms can be further described as arising from two situations. The first and most common situation is when the symptoms are from what would traditionally be called a “healing reaction”—the organism’s concerted and organized attempt to defend and heal itself (i.e., the organism’s homeostatic process). These healing reactions produce what can be called “homeostatic symptoms.” Examples are fever and inflammation in infections, almost any reaction of the immune system, and many of the symptoms of chronic disease. This interpretation of symptoms is generally ignored by mechanism. Instead, it views a symptom as the result of a destructive process and focuses on intervening by relieving the symptom or manipulating the pathological mechanism. Mechanistic medicine is therefore most often working contrary to homeostasis and the organism’s attempt at healing (this is usually its intent). When this therapeutic approach is effective, vitalists call the result a “suppression” (Box 5.3). This approach to health care is so pervasive that most people, lay and professional alike, still think nothing of suppressing mild fevers with antipyretics. In contrast, vitalism considers these homeostatic symptoms to be the product of a constructive phenomenon and therapeutically stimulates and encourages this directed healing process. In contrast, vitalism considers these symptoms to be the product of a constructive phenomenon and therapeutically stimulates and encourages this directed healing process. Rather than simply trying to

Suppression: Suppression is when: (a) a treatment is given for a disease; (b) the signs and symptoms of the disease go away; (c) the treatment is removed and the signs and symptoms stay away; but (d) the whole person is less healthy. Although the symptoms of concern are better, the whole person is worse, which leads to more and worse disease in the future. In conventional medicine suppression is often a goal. Alternative medicine tries for a higher standard, but because palliation is often what happens, suppression can occur here, too. Suppression frequently occurs because a treatment is given for a symptom or disease rather than the whole person being treated. Suppression may lead later to another more invasive illness. Healing: Healing is what a living organism (body–mind) does, or attempts to do, for itself. A treatment can only: (a) control signs and symptoms (palliate or suppress); (b) support life in a crisis (palliate or suppress); (c) attack an invading organism such as bacteria or remove a pathological agent such as a toxin or allergen (palliate); (d) mechanically repair tissues that have been damaged or are malformed (palliate); or (e) support and/or stimulate the organism’s innate healing processes while the body–mind does the work of healing itself (cure). Curative treatment involves stimulating the whole organism to heal itself. The palliation and suppression of symptoms does not help stimulate self-healing. Palliation tends to create the opposite effect and suppression actually gets in the way of the whole body–mind’s efforts to self-heal.

eliminate a pathogenic agent, as mechanistic therapy might, vitalism focuses more on augmenting the organism’s resistance to that agent. That is not to say that vitalists object to removing the agent, only that it should be done in the context of simultaneously increasing resistance (in other words, decreasing susceptibility). The importance of this approach becomes evident when one recognizes that disease is only possible when both a pathogenic agent and a susceptibility to that agent are present. Healing reactions can take several forms. In the first type, an organism’s response to a pathogenic agent does not produce symptoms. When the organism is capable of easily defending itself from the agent, no symptoms are perceivable. This is a common homeostatic process and is demonstrated when a potential pathogen, such as β-hemolytic streptococcus, is cultured from a healthy person’s throat. However, when the organism is more susceptible or the relative strength of the pathogenic agent is greater, a threshold is reached and symptoms become perceivable. Successful healing reactions of this type include vigorous acute diseases that quickly resolve. The early naturopaths would have called these acute reactions “healing crises.” As the susceptibility of the organism increases relative to the strength of the pathogenic agent, there is a greater likelihood that the healing attempt will not be successful. When such a reaction is unsuccessful but vigorous, death may result, unless there is timely application of vitalistic or mechanistic therapy. Examples of this situation are acute bacterial meningitis and cholera. When the healing attempt is feeble and therefore ineffective, the reaction usually goes into the “chronic disease” stage. Vitalists observe that suppression seems to increase the likelihood that the reaction will be forced to go into such a chronic stage. In this situation the reaction is “smoldering,” and most often the organism cannot overcome the

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pathogenic agent unassisted. It just “holds its own,” and as the organism’s general health decreases over the years, the reaction gradually degenerates, producing symptoms that become less homeostatic as it moves to an end-stage pathology. Palliating the symptoms during this phase of the disease contributes to the declining health over time because palliation means that the underlying susceptibility or problem is not being addressed in a curative manner. If the organism can be therapeutically stimulated to produce a more vigorous healing reaction, it can often successfully complete the original healing attempt. This augmented reaction is another example of a naturopathic healing crisis and would also be called an “aggravation” by the vitalists who practice homeopathic medicine. Intervening mechanistically by relieving symptoms does little to stimulate or encourage the healing response; it usually actually inhibits the healing response. In contrast, vitalistic therapies can be very effective in helping these healing reactions, because the goals of such therapies are precisely the same as those of the organism. Thus it is thought that vitalistic medicine works because, by honoring this process and thereby strengthening the whole organism, it encourages a more effective healing effort. Ideally, the organism is then able to accelerate and complete its reaction against the pathogenic agent, leading to the permanent disappearance of the symptoms as it returns to a state of health. It would be naive to say that every stage of the healing reaction is positive and in the best interest of the organism or that no symptoms should be palliated. The modern vitalist acknowledges that palliative intervention is sometimes necessary. In contrast, it is important to note that routine mechanistic intervention can encourage its own worstcase scenarios. When mechanistic therapies successfully suppress an organism’s chosen healing reaction, a less effective and less desirable response is often produced. Therefore when suppression occurs, it can lead to a more complicated medical situation. Consequently, the very practice of mechanistic medicine tends to reinforce its practitioner’s conviction that such intervention is usually necessary. It should be noted, however, that not all mechanistic intervention leads to suppression. It happens less often when the pathogenic agent can be readily eliminated, such as the use of an antibiotic in nonrecurring acute bacterial infections, or when relatively noninvasive therapies are used, such as natural medicines. The second type of symptom-producing situation occurs when the organism produces symptoms in response to an organic lesion that arises from the direct pathological influence of a pathogenic agent. These could be called “morbid symptoms,” examples of which are symptoms from the mass of an invasive tumor, shortness of breath from emphysema, and pain of an injury or myocardial infarction. It should be mentioned that even these symptoms are the result of the organism’s overall effort to maintain homeostasis, and homeostatic symptoms are also often present. In addition, a morbid symptom is not necessarily without utility. For instance, pain is valuable as an indication of tissue damage. As can be seen, many, if not most, of these situations involve end-stage disease. Here mechanistic therapies can be very positive when the goals of the therapy do not conflict with those of the organism. There are instances when invasive mechanistic intervention will probably be required to save “life and limb.” These include such conditions as birth and genetic defects, serious traumatic injuries, crisis situations, overwhelming infections, and many malignancies. Unfortunately, mechanistic intervention does not guarantee a successful outcome either. Even in these situations, however, the effectiveness of vitalistic and natural therapy should not be underestimated, and their concurrent use will certainly augment any mechanistic intervention.

The concept of homeostatic and morbid symptoms can be a useful tool to help the understanding of the healing and disease processes, but in many situations it may not be possible to categorize the type of symptoms produced. A rough rule of thumb, however, would be that virtually all symptoms accompanying reversible or functional diseases are homeostatic. In contrast, many of the symptoms associated with traumatic injury and end-stage pathology would be morbid symptoms. 

Scientific Medicine Although mechanism and vitalism represent opposing perspectives, the systems of medicine that represent these philosophies can be successfully tested and examined with the scientific method.1 That is not to say that the philosophy of vitalism has been unquestionably proven—only that the validity of vitalistic interventions can be scientifically demonstrated. If a therapy can be proven effective, the effectiveness implies the accuracy of the philosophy on which it is based. Unfortunately, very few of the vast resources of the biomedical community have been directed toward investigating vitalistic medicine. Conventional medicine, as the dominant health care system and a representative of mechanism, has claimed for itself the title “scientific medicine.” However, it is inherently no more or less scientific than vitalistic medicine. A system is scientific only when it has met the criteria of the scientific method. This method requires the collection of data through observation and experimentation and the formulation and testing of hypotheses. Nonprejudicial science can effectively study any system, but the researcher must understand the system’s particular paradigm. Experiments on a vitalistic therapy based on a reductionistic and mechanistic model are not going to be constructed to show success, or if they do show success, it will be entirely fortuitous. The criteria of the scientific method can be met by vitalistic medicine, but only when the researchers recognize that it cannot be studied as though it is reductionistic or based on a simplistic model of linear causality. When the experimental model acknowledges the complexity of a living system in a social context (i.e., holism and circular causality/feedback loops), vitalistic medicine proves to be both verifiable and reproducible and, thus, scientific. Unfortunately, because of its current political and economic dominance, conventional medicine is in the position to dictate (through economic and publication control) that research, and therefore the scientific method will be applied primarily to itself. The result is that most conventional practitioners dismiss vitalistic medicine, along with all alternatives, as unscientific. Ironically, most vitalistic physicians also have extensive training in mechanistic and/or conventional medicine. Generally, they are capable of practicing mechanistically and do so to greater or lesser degrees. 

NATUROPATHIC PHILOSOPHY Vis Medicatrix Naturae Naturopathic physicians assert that all true healing is a result of vis medicatrix naturae (the healing power of nature). Unfortunately, some people in the field of alternative medicine (including some naturopathic physicians and students) have mistakenly translocated this concept to the therapy. These practitioners tend to operate as though this “healing power” is an intrinsic property of the natural therapy or medicinal substance itself. In contrast, proponents of vitalism and naturopathic medicine have always understood that the “healing power of nature” is an inherent property of the living organism. Vis medicatrix naturae is the living organism’s “desire” and ability to heal itself. As mentioned, the homeostatic process best exemplifies this. Historically, naturopathy is a vitalistic system of medicine. However, over the past 130 years its eclecticism has allowed it to incorporate a

CHAPTER 5  number of therapies that can function mechanistically. What makes these mechanistic therapies acceptable, given naturopathic medicine’s vitalistic foundation, is the emphasis on meeting each patient’s pragmatic health care needs. So the application of vis medicatrix naturae in practice is constantly adjusted depending on the situation at hand. Ideally, naturopathic practice involves only the use of therapies that support the organism and encourage its intrinsic healing process to work more effectively while avoiding the use of medicines and procedures that interfere with natural functions or have harmful side effects. Natural medicines and therapies are therefore preferred, because when they are used properly and in appropriate circumstances, they are the least harmful, least invasive, and best able to work in harmony with the intrinsic natural healing process. In addition, their constituents have been encountered in nature for millions of years. This long period of exposure has enabled the body to develop metabolic pathways capable of effectively using, processing, and detoxifying these medicines. The total organism is involved in the healing attempt, so the most effective approach to diagnosis and treatment is to consider the whole person. In addition to physical and laboratory findings, important consideration is given to the patient’s attitude, psychological and spiritual state, social circumstances, lifestyle, diet, heredity, and environment. Careful attention to each person’s unique individuality and susceptibility to disease is critical to the proper evaluation and treatment of any health problem. Naturopathic physicians contend that most disease is the direct result of the ignorance and violation of what would be traditionally called “natural living laws.” These general lifestyle rules (including diet) are based on the concept that there is an environment (both internal and external) that optimizes the health of an organism. Analysis of the lifestyles of Paleolithic and healthy primitive and modern cultures gives naturopathic physicians and their progenitors many clues as to what a healthy lifestyle should involve. Throughout most of modern history, biomedical science has focused primarily on researching the sick. Recently it has finally begun to evaluate what constitutes a healthy lifestyle. To no one’s surprise, this lifestyle looks like the same one advocated by naturopaths for the past 130 years. A healthy lifestyle could be generalized to include the following: • Consuming natural unrefined foods • Getting adequate amounts of exercise and rest • Living a moderately paced lifestyle • Having constructive and creative attitudes • Connecting to other people socially • Being present to the spiritual aspects of life • Avoiding toxins and polluted environments • Maintaining proper elimination It is also important to control these areas during illness to remove as many unnecessary stresses as possible and to optimize the chances that the organism’s healing attempt will be successful. Therefore patient education and responsibility, lifestyle modification, and preventive medicine are fundamental to naturopathic practice. Although the practice of naturopathic medicine is grounded in vis medicatrix naturae, it also recognizes that mechanistic intervention in the disease process is sometimes efficacious and, at times, absolutely necessary. Therefore naturopathic physicians treat patients with a wide variety of vitalistic and mechanistic therapeutic modalities. It is the circumstances and the goal of the therapy that ultimately determines which approaches are used. Naturopathic physicians have a long-standing tradition of integrating the best aspects of traditional, alternative, and conventional medicine in the interest of the patient. As appropriate, patients are referred to other health care practitioners. Whenever possible, every effort is made to use all treatment

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techniques in a manner that is harmonious with the naturopathic philosophy. 

Natural Medicines and Therapies Traditionally, medicines administered and prescribed by naturopathic physicians have been primarily natural and relatively unprocessed. Four categories of natural medicines can be defined. The first consists of substances found in nature that have been only minimally processed. Examples include, but are not limited to, foods, clean air and water, and whole herbs. The early “nature cure” practitioners used this category primarily. The second category involves agents extracted or made from naturally occurring products. Although these medicines have undergone processing, their constituents are still in the form found in the original natural substance. These first two types of natural medicinal substances have synergistic constituents that allow their use at lower doses with a resultant broader and safer therapeutic index. Examples of this category are tinctures and other botanical extracts (some of which are standardized on one or more constituents known to be clinically effective), homeopathic medicines, glandular extracts, and other substances of animal origin. The third category of natural medicines comprises those highly processed medicinal substances that are derived from a natural source. Often everything has been removed from such substances but the identified active ingredient, and they no longer have any synergistic constituents. Examples of these are the many new nutraceuticals made from plant substances, constituents of biochemical pathways, enzymes, amino acids, minerals, vitamins, and other food extracts. The fourth category that may be considered natural are those manufactured medicines that are presumed to be identical to naturally occurring substances. They have the advantage of being less expensive and are typically available in higher concentrations. Examples of these manufactured natural medicines include bioidentical hormones, synthetic vitamins, and analogues of plant and animal constituents. However, their use is a compromise because: • It is difficult to determine whether they are the equivalent of the natural product. • They lack natural synergistic components. • They may include contaminants from the manufacturing process; these contaminants are often chemically and structurally similar to the desired medicine but generally interfere with the normal pathways rather than enhance them. Naturopathic physicians also use many natural physical therapies. What makes a therapy natural is that it is derived from a phenomenon of nature and is used to stimulate the body to heal itself. Examples of these phenomena are air, light, heat, electricity, sound, and mechanical force. Some of these natural therapies are mechanical and manual manipulation of the bony and soft tissues (naturopathic manipulative therapy), physiotherapy modalities (e.g., electrotherapy and ultrasound), hydrotherapy, and exercise therapy. Naturopathic physicians also use lifestyle modification, counseling, and suggestive therapeutics. These therapies are all discussed in more detail in other chapters. 

Family and Specialty Practice Naturopathic physicians, like other types of primary care providers, develop practices that meet their personal interests and skills. Although most are engaged in general and family practice, some also specialized in particular therapeutic modalities and/or types of health problems. In all situations, however, the emphasis is still on treating the whole person. The practice of family medicine requires the use of some medicines, techniques, and devices that are not natural but belong among the comprehensive family practice services offered by the naturopathic profession.

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In the modern era of naturopathic medicine many states have expanded the scope of practice so that naturopathic physicians now practice much like other primary care practitioners with pharmaceutical prescribing rights. However, naturopathic physicians generally approach the use of pharmaceuticals differently than conventional physicians. They are seen as temporary interventions to be used to support the patient while other, more vitalistic natural therapies are used to help the patient recover his or her health with the ultimate goal of no longer needing the pharmaceutical. Many naturopaths have also developed advanced expertise in specific natural therapeutic modalities. These practitioners have usually invested in postgraduate training, such as that available through residencies. Three therapeutic specialties that merit mention are natural childbirth, acupuncture, and homeopathy. There is also a growing trend of specializing in organ systems (e.g., gastroenterology) or diseases (e.g., cardiology). 

THE PHILOSOPHICAL CONTINUUM When the various healing systems are examined and placed on a philosophical continuum, mechanism and vitalism are on different ends of the same health care spectrum. Both ends of this health care continuum have their strengths and weaknesses. Mechanistic medicine is effective for trauma, crisis care, end-stage disease, and many acute disorders. However, it is clearly a failure for most chronic disease. Conventional medicine considers most chronic diseases incurable. Vitalistic medicine, in contrast, has its most dramatic successes with chronic disease and is effective with many kinds of acute disease. It is not very effective with trauma and crisis care or with end-stage disease, although it can be a very useful complement to conventional medicine. As can be seen, both ends of the health care spectrum are necessary if every patient’s health care needs are to be met. Although aspects of naturopathic medicine (e.g., constitutional hydrotherapy) and conventional medicine (e.g., chemotherapy) represent the archetypes of vitalism and mechanism, the space between the ends of this spectrum is a gray area within which both naturopathic and conventional physicians operate on a continual basis. Naturopathic physicians integrate vitalistic therapies with mechanistic therapies, but it is not possible for everyone to be experts in everything.

The vast majority of naturopathic or conventional physicians cannot learn and competently practice all types of health care. Consequently, to effectively meet society’s health care needs, it is necessary to create an integrated/collaborative health care system. Such a system would have both vitalistic and mechanistic practitioners working together in the same clinical settings. The trends of popular culture and biomedical science that are finally beginning to study alternative medicine suggest that the creation of an integrated health care system is now well under way. However, it takes no great skill for a mechanistic medical doctor to switch from giving a synthetic drug for a disease to giving a natural medicinal substance (both mechanistically oriented interventions) without understanding vitalistic thinking. If naturopathic medicine becomes just another mechanistic system using natural medical substances to treat disease (instead of a system identified with treating the whole person vitalistically), it will lose its unique niche in an integrated health care system. To survive and thrive in this new environment, naturopathic medicine must keep its vitalistic roots. With a thorough grounding in vis medicatrix naturae, modern naturopathic medicine will flourish and achieve a leadership position as the dominant health care paradigm shifts to the integrated medicine of the future. 

CONCLUSION The practice of naturopathic medicine can be summarized most simply as helping the body–mind heal itself in the least invasive, most fundamentally curative manner possible. This approach is not tied to any particular therapy or modality, but rather is oriented to a rational blend of vitalistic and mechanistic principles working with the whole person and educating the patient in the ways of health. As naturopathic knowledge of health and disease grows, new therapies and approaches to health care will be added as they satisfy the principle of vis medicatrix naturae. With integration of the larger health care system, naturopathic medicine’s place is assured as the profession that truly understands each unique human being’s power to heal.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. A thorough review of all health care modalities in use today reveals some that could be considered metaphysical. These include such things as prayer, faith healing, psychic healing, healing touch, touch for health, and medical dowsing. Generally speaking, the actual operator of the therapy must call on God or have some special endogenous skill or “power” that goes beyond intellectual knowledge. This makes these modalities “operator-dependent” and, thus, cannot be validated separately from the practitioner—greatly increasing the difficulty of their scientific verification. Consequently, these modalities are not historically relevant to this discussion of medical philosophy.

FURTHER READING Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol. 1992;13:369–383. Coulter HL. Divided Legacy. Richmond, CA: North Atlantic Books. Coulter HL. Homeopathic Science and Modern Medicine. Richmond, CA: North Atlantic Books. Dubos R. Mirage of Health: Utopias, Progress, and Biological Change. New York: Harper.

Kirchfeld F, Boyle W. Nature Doctors: Pioneers in Naturopathic Medicine. Portland, OR: Medicina Biologica. Lindlahr H. Philosophy of Natural Therapeutics. Maidstone, Kent, UK: Maidstone Osteopathic Clinic. McKee J. Holistic health and the critique of western medicine. Soc Sci Med. 1988;26:775–784. McKeown T. The Role of Medicine: Dream, Mirage or Nemesis? Oxford: Basil Blackwell; 1980. Payer L. Medicine and Culture: Varieties of Treatment in the United States, England, West Germany, and France. New York: Henry Holt and Company. Schubert-Soldern R. Mechanism and Vitalism: Philosophical Aspects of Biology. South Bend, IN: University of Notre Dame Press. Selys H. The Stress of Life. New York: McGraw-Hill. Sinnott E. The Bridge of Life: From Matter to Spirit. New York: Simon and Schuster. Spitler HR. Basic Naturopathy: A Textbook. New York: American Naturopathic Association. Zeff JL. The process of healing: a unifying theory of naturopathic medicine. J Nat Med. 1997;7:122–125.

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6 Placebo and the Power to Heal Peter W. Bennett, ND

OUTLINE Introduction, 87 Placebo Response, 88 Why study the placebo effect?, 88 History of Placebo, 89 Origin of the Term Placebo, 89 Clinical Observations of “Known” Placebo Therapy, 89 Other Clinical Observations, 90 Placebo Myths, 90 Myth 1, 90 Myth 2, 90 Myth 3, 91 Myth 4, 91 Pharmacodynamics, 91 Packaging and Delivery, 91 Placebo Interactions, 91 Placebo Healing Mechanisms, 92 The Role of Emotions, 92

The Vis Medicatrix Naturae, 92 Conscious Control Over Homeostasis, 92 Neurophysiology of Placebo Response, 93 Placebo and Stress Physiology, 93 Physiological and Psychological Stress, 94 Endorphins, Hormones, and Neuropeptides, 94 Clinical Application, 95 Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care, 95 Tollem Causum: Remove the Cause of Disease, 95 Support the Therapeutic Relationship, 96 Enhance Positive Emotional States, 96 Implement Therapeutic Conditioning or Learning, 98 Use Altered States of Consciousness, 99 Ethics, 101 Conclusion, 101

INTRODUCTION

As time marches on, medicine is beginning to acknowledge, stimulate, and utilize the subliminal healing capacity of the mind. A review of the placebo literature in Lancet2 concluded that the placebo effect has a complex physiological multisystem dimension and should be encouraged in the clinical situation to optimize health and healing—a perspective reached by this author 30 years ago and published in the first edition of this textbook. In November 2000, 17 health centers and agencies gathered together for 3 days to explore the science of self-healing hidden in the power of placebo. This conference focused on the powerful mind–brain physiology of the placebo effect and its potential for affecting the course of human disease.3 One of the conclusions of the conference was that the “placebo response” has potential use for medical application and needs further exploration. Research has shown that the impressions and thoughts in a patient’s mind, the attending physician’s intention, and the combined effect of their relationship have a measurable effect on the health of the patient. The ability of the patient’s mind to affect the process of virtually every disease has been well documented,4,5 and the internal mechanisms and pathways by which the mind can positively or negatively affect the immune and healing processes has been investigated in the scientific literature of psychoneuroimmunology.6,7 As the body of knowledge documenting the critical role of the patient’s psyche in the therapeutic environment has grown, it has become increasingly important for all schools of medicine to teach the healing potential of the human mind. Conventional medical thinking has turned its opinion of the placebo effect from that of a 19th-century pejorative to a concept that sums up the complex mind–body interactions affecting the power of

As living organisms, we have evolved with an innate capacity for self-healing. In the clinical setting, naturopathic physicians have always relied on this self-healing capability of the individual. The healing power of the mind and body, the “life force,” is a cornerstone of naturopathic philosophy and treatment. Naturopathic physicians describe this with a phrase attributed to Hippocrates: vis medicatrix naturae. The “inner” power to heal is one of the great mysteries of medicine, and it behooves us as physicians, regardless of our licensing body, to understand the biology and physiology that surround the processes that guide and control this phenomenon. Following this logic, a central problem to be explored and considered is that placebo response has shown medical science that the mind of a patient has a powerful role in therapy. Although the dictionary definition of mind is described as a person’s thoughts and consciousness, centuries of writings from many societies and cultures on philosophy, religion, psychology, cognitive science, neuroscience, and artificial intelligence have struggled to clearly define the complex interaction of personality, emotion, perception, memory, thinking, judgment, and spiritual insight. Adding to the difficulty of the semantics of exploring the healing power of the mind is the difficulty to definitively define the scope of physiology and function of the mind.1 Because the definition and understanding of the human mind challenge a consensus of our collective insight and understanding, it is natural that the function and uses of placebos are an area of myth and misunderstanding rather than an area of wisdom and insight.

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people to heal.3 Unfortunately, the most modern abuse of the concept of the placebo comes from biased critics of alternative medicine who have chosen to label the beneficial effects of these therapies as merely from the placebo. These critics dismiss the science of natural healing as an imaginary phenomenon and the last resort for quack doctors who have no real medical treatments to offer their patients.8 The most interesting aspect of the placebo literature is the exploration of the extent of the potential of the mind to influence human health. The “power of placebo” draws on the innate ability of the body to spontaneously heal itself, a fundamental principle of naturopathic medicine. This point separates the care delivered by naturopathic physicians from the pharmaceutical and surgical approaches of current medical “standard-of-care” procedures. If common medical texts on internal medicine or ambulatory care are examined, the word healing is not found in the index. Except for the diagnostic evaluation of “self-limiting diseases” and “spontaneous regression,” the ability of the human organism to self-right and repair from a state of acute or chronic disease is not explored in modern medicine except under the designation “placebo response.” The placebo response therefore represents all the “unknown” variables that conspire to heal a patient despite pharmaceutical and surgical intervention. Although it seems to be a natural area to develop in clinical and hospital settings, the fundamental separation of mind and body in conventional medical thinking may be slowing down a standardization of care that actively engages the hopes and beliefs of all patients undergoing treatment. 

PLACEBO RESPONSE The placebo response represents the power of the mind, through intention, to effect (1) a change in oneself, (2) a change in those around one, and (3) a change in the environment in which one lives. Intention has been observed to affect machines9 and remote biological systems.10 Distantly influenced systems include another person’s electrodermal activity, blood pressure, and muscular activity; the spatial orientation of fish; the locomotor activity of small mammals; and the rate of hemolysis of human red blood cells. Prayer, an example of intention, has been extensively studied as a therapeutic healing modality.11 One study showed a dramatic result in cardiac intensive unit recovery when patients were prayed for by someone at a distant location.12 Patients in this study were 5 times less likely to require antibiotics, 3 times less likely to experience pulmonary edema, 12 times less likely to require endotracheal intubation, and significantly less likely to experience cardiac mortality. Our biological systems must conform to the laws of physics. Modern physics has investigated the effect of an observer on the system observed. It has been shown that an electron will acquire a definite axis of measurement in the process of measurement. Bell’s theorem supports the idea that our universe consists of particles unified instantly as an indivisible whole; our biological homeostatic systems cannot be analyzed in terms of independent parts. The interconnected nature of our biological systems has been known for thousands of years; the ancient Buddhist concept of “interdependent phenomena” or Pratītyasamutpāda accurately describes this paradigm. The Buddhist concept of interconnectedness and interdependency does not imply a Newtonian billiard-ball effect of a cause or causation, but rather an interdependent “held” state of a plurality of conditions and causes. The idea that a healing response can be generated without genuine causation, such as drug treatment, seems to violate the laws of biological systems. Comparing the healing response generated by a thought or intention might not violate the laws of physics, but it has a difficult place in a medical philosophy of cause and effect driven by pharmacodynamics. Interestingly, humans are not the only organisms to be

affected by the placebo response; it has been observed in Caenorhabditis elegans and the fruit fly Drosophila melanogaster through cell signaling indicating a phenotypic response to sensory input, which shows that the placebo phenomenon is not ignoring cause and effect—it merely indicates the potential for more subtle self-regulation than that referenced in modern medical standards of care.13 Our current medical system is gradually shifting with the developments in modern physics. These modern ideas of biological systems are diametrically opposed to Cartesian paradigms that our internal and external environment consists of separate parts joined by local connections. Medicine must take a “quantum leap” to catch up with the knowledge we possess about our environment through quantum physics. We can see clearly that it is impossible for a doctor to observe a patient without that observation having an effect on the health of the patient. Pierre Teilhard de Chardin postulated, and Rupert Sheldrake proved, the possibility of a “morphogenetic field” for the subliminal communication to all members of our species.14 The effect of human thought on other members of society has been described in human society since the beginning of our earliest cultures. Naturopathic physicians believe that the body has a powerful ability to maintain health and repair to a healthy state after disease by virtue of its inherent power of vitality. This homeostatic healing mechanism has been selected by nature in the same way that the organs that we consider to be vital to our survival have been selected. Healing happens unaided by simply maintaining an environment that does not obstruct the path of cure. Because the placebo literature documents the philosophical foundations of the naturopathic healthcare model, it is important to review the full scope of this subject. Integrating known placebo initiators in clinical practice is essential for good patient care. 

WHY STUDY THE PLACEBO EFFECT? For hundreds of years, physicians have watched their patients respond to therapies with a wide range of results. Some patients recover fully, whereas others, with apparently identical diseases and therapies, wither and die. Today, a skilled physician can correctly diagnose the condition of a patient by applying the sophisticated techniques of modern medicine. Then, an appropriate therapy, the efficacy of which has been thoroughly proven in research and clinical trials, can be prescribed. Through this process the patient will have received the best care available through current medical technology. However, if the diagnosis, therapy, and therapeutic interaction do not stimulate the hope, faith, and belief of the patient, the chances of success are measurably diminished. In the literature on the placebo effect15; psychoneuroimmunology6; and psychosomatic,16 behavioral,17,18 and psychiatric19 medicine, it has been repeatedly demonstrated that the beliefs of both the patient and the doctor, and their trust in each other and the process, generate a significant portion of the therapeutic results.20 The placebo and its effect are not separate from any aspect of the therapeutic interaction, nor are they “nuisance variables” muddying a clear clinical picture. Rather, they send the physician a strong message: it is a patient’s own belief system that mobilizes the inherent healing powers of the mind. By studying the placebo effect, a physician is better able to fully harness this power to trigger internal healing mechanisms. Yet despite the quantity of documentation, the placebo effect remains one of the most misunderstood areas in modern medicine. The physician should always strive to stimulate self-healing, or the placebo effect, as fully as possible to maximize its potential for healing. Someday physicians will be able to explore the deepest recesses of the unconscious to directly access therapies that assist the body in the

CHAPTER 6  restoration of internal homeostasis. The optimal model for health care is the marriage of appropriate medical technology with the factors that have been shown to generate the placebo effect. This exciting scenario shines on the horizon as the health care of the future. Because the doctor–patient relationship is such fertile ground for stimulating the healing response,21–23 it serves a physician well to comprehend the nature of the placebo phenomenon to fully realize this potential for healing. 

HISTORY OF PLACEBO Both the modern physician and primitive medicine men and shamans of the past used ineffective therapies to stimulate healing in their patients. As Shapiro observed, “the true importance of placebo emerges with a review of the history of medical treatment.”24 It was noted that the historical therapies of the medical profession and traditional healers, “purging, puking, poisoning, puncturing, cutting, cupping, blistering, bleeding, leeching, heating, freezing, sweating, and shocking,”25 worked because of the placebo effect. Although these practices might seem ludicrous in retrospect, all of these therapies were once considered effective. As an embarrassing epilogue, the placebo literature shows that ineffective procedures are just as pervasive in modern medicine as in the jungle hut of the shaman. We must therefore ask ourselves how unfounded medical therapies can survive peer-reviewed literature and centuries of cultural acceptance. The power of the patient’s belief in the potential for a cure has been consistently observed throughout history. Both Galen and Hippocrates recognized the strong effect of the mind on disease and recommended that faith, treatment ritual, and a sound doctor– patient relationship could provide important therapeutic results.26 Recognition of the power of positive expectation was recorded frequently in the medical literature of the 17th and 18th centuries. It was in the 18th century that the use of placebos was first defined as a “commonplace method of medicine.”27 As the importance of drug therapy grew in the 19th century, the term placebo became identified with medicines involving substances that resembled drugs. However, in the 1940s, because of the increase in double-blind research, it became associated with inert substances that were used to replace active medication. 

ORIGIN OF THE TERM PLACEBO The original Latin meaning of placebo is “I shall please.”28 Although the term had a purely medical application in the first half of the 20th century, its meaning has been subject to various interpretations throughout the past several hundred years. Before the 1940s, placebos were pharmacologically inactive substances, such as saline and lactose pills, used to satisfy patients that something was being done for them—in other words, the doctor was “pleasing” the patient. The 1940s and 1950s saw an explosion of the use of double-blind experimental procedures to evaluate the growing number of new drugs and medical procedures. Suspicion arose that all medical therapies contained an element of the placebo phenomenon.29 This new understanding pressed the scientific community to offer new, far broader definitions. Shapiro25 offered the classic definition of a placebo: Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without

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BOX 6.1  Types of Placebos 1. Known placebo: Placebo used in a single-blind experiment. The doctor knows it is a placebo, but the patient does not. 2. Unknown placebo: Double-blind use of placebo. Neither the doctor nor the patient knows that the medication is a placebo. 3. Active placebo: Any substance that has an intrinsic physiological effect that is irrelevant to the ensuing placebo effect. The vasodilating effect of niacin would make it a good active placebo. 4. Inactive placebo: Any substance that is used with medicinal intent but that has no inherent physiological effect. Aside from the glucose effect in a sugar pill (or, to complicate things, an allergic reaction to some component of the supposedly inert substance), it has no physiological effect. 5. Placebo effect: Any changes that occur in a patient as the result of placebo therapy. 6. Nocebo effect: Any changes that occur as a result of placebo therapy that are perceived as negative or counterproductive to the path of cure.

the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific—oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psychotherapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occur and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research. A more accurate definition would be the following: The placebo effect is the process of a physician working with the self-healing processes of a patient. The placebo response is healing that results from the patient’s own natural survival and homeostatic defense mechanisms. Modern placebo definitions extend to its nature, properties, and effects. A placebo can be known or unknown, active or inactive, positive or negative in results (placebo effect vs. nocebo effect), and can extend to all forms of diagnostic or therapeutic modalities,30 as further defined in Box 6.1. 

CLINICAL OBSERVATIONS OF “KNOWN” PLACEBO THERAPY One of the more dramatic examples of the placebo effect reported in the medical literature involved a patient with advanced lymphosarcoma, which Klopfer31 reported was highly susceptible to the patient’s faith in an experimental drug called Krebiozen. When the patient was started on the drug injections, his enthusiasm was so intense that “The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”31 The injections were continued until the patient was discharged from the hospital and had regained a full and normal life, a complete reversal of his disease and its grim prognosis. Within 2 months of this recovery, reports that the drug Krebiozen was ineffectual were leaked to the press. Learning of this report, the patient quickly began to revert to his former condition. Suspicious of the patient’s relapse, his doctors decided to take advantage of the opportunity to test the dramatic regenerative capabilities of the mind; a single-blind study was performed on the patient using pure placebo. He was told that a new version of Krebiozen had been developed that overcame the difficulties described in the press, and some of the drug was promised to him as soon as it could be procured.

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BOX 6.2  Symptoms and Side Effects of

Placebo Response

• Anger206 • Anorexia51 • Behavioral changes207 • Depression62 • Dermatitis medicamentosa51 • Diarrhea51 • Drowsiness62 • Epigastric pain51 • Hallucinations56 • Headache208 • Lightheadedness51 • Palpitation51 • Pupillary dilation36 • Rash51 • Weakness51

With much pomp and ceremony, a saline water placebo was injected, increasing the patient’s expectations to a fevered pitch. The recovery from his second near-terminal state was even more dramatic than the first. Tumor masses melted, chest fluid vanished, he became ambulatory, and he even went back to flying again. At this time he was certainly the picture of health. The water injections were continued because they worked such wonders. He then remained symptom-free for more than 2 months. At this time, the final American Medical Association announcement appeared in the press—“nationwide tests show Krebiozen to be a worthless drug in the treatment of cancer.” Within a few days of this report, the patient was readmitted to the hospital in extremis. His faith was now gone, his last hope had vanished, and he succumbed in less than 2 days.31 Other famous placebo case studies are one reported by Cannon32 on “voodoo death” caused by belief and one reported by Kirkpatrick,33 who documented the spontaneous regression of lupus erythematosus resulting, in part, from the patient’s belief in the removal of a curse.

Other Clinical Observations Belief sickens, belief kills, belief heals.34 Evans35 and Beecher36 reviewed, between them, 26 double-blind studies on the efficacy of active analgesic drugs in the treatment of pain. Independently, they concluded that 35% of patients with pain experienced a 50% reduction in their symptoms after placebo medication. These were particularly remarkable results when viewed in the context of Evans’s observation that with a standard dose of morphine, only 75% of the patients experienced a 50% reduction in pain. In calculating the efficiency index of placebo analgesia, a method often used to determine the relative efficiency of drugs, placebo was 0.56 as effective as a standard dose of morphine. This prompted Evans to remark, “Thus, on average, placebo is not a third as effective as a standard injection of morphine in reducing severe clinical pain of various kinds but is in fact 56% as effective.”35 As discussed previously, the placebo phenomenon has been evaluated in a wide variety of clinical settings in addition to pain management (Box 6.2). When a phenomenon such as the placebo effect has been observed to be active in diverse clinical situations, such as surgery, drug therapy, psychotherapy, and biofeedback, and over a range of physical and mental symptoms, the conclusion that it must be a factor in all aspects of medicine is inescapable.

In addition to the variety of positive effects that placebos produce are the nocebo effects, perceived as counterproductive to the therapeutic goals. Widely ranging negative side effects to placebos have been reported in the medical literature.37 These side effects are frequently consistent with those of the medication that patients believe they are getting. For example, the studies that measure the effects of a supposed aspirin usually show nocebo effects of ulcerlike pain.38 One study showed that suggestion seems to be a primary cause of nocebo reactions, in contrast to the strong conditioning component found in the placebo response.39 In homeopathy, aggravations and ameliorations are commonly seen when a placebo is given to fend off a patient’s need to take a medication while the homeopathic physician is waiting to see whether a high-potency remedy will effect a cure. Homeopathic doctors report that placebos can cause anxiety and loneliness as well as calmness and immediate relief from insomnia.40 

PLACEBO MYTHS An investigation of the understanding of placebos found in the current medical literature revealed the misconceptions that prevail about the nature of placebo therapy and its effectiveness.40 A study undertaken to examine doctors’ and nurses’ attitudes about the efficacy and use of placebos showed that both groups underestimated the number of patients who could be helped by placebo.41 Physicians showed a consistent pattern of placebo use, as follows: • Placebos were used to prove the patient wrong through the diagnosis of psychogenic symptoms in patients who were thought to be exaggerating, imagining, or faking their symptoms. • Placebos were used in the treatment of alcoholic, psychotic, and demanding patients who were disliked by the staff of the hospital. • Placebos were used as a treatment in situations in which standard treatments failed or the patient was getting worse. These misconceptions regarding the nature of the placebo accounted for its widespread misuse in patients who were perceived as uncooperative or who were suspected of malingering. Myths about placebos continue to hinder a full understanding of the power inherent in this aspect of health care. The most common myths are discussed here.42

Myth 1 “Because placebos tend to be physiologically inert, it is not possible for them to have an effect on physiological homeostasis.” Fact: Research shows that placebos have a wide range of effects (Table 6.1) that are found throughout all aspects of human physiology. 

Myth 2 “Placebos are useful only with symptoms that are associated with psychological or psychosomatic complaints. Patients who need a placebo are hypochondriacs with vivid imaginations and need to be palliated with something to please them.” Fact: Placebos have been shown to be effective in the care of all types of patients, with a consistent level of positive results for a wide variety of accurately diagnosed diseases. Beecher20 was one of the first to compile a listing of the therapeutic effectiveness of placebo, thereby uncovering the wide range of therapeutic applications that were previously thought to be limited only to pain control. He concluded, “there is too little scientific as well as clinical appreciation of how important unawareness of these placebo effects can be and how devastating to experimental studies as well as to sound clinical judgement lack of attention to them can be.”20

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Placebo and the Power to Heal

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TABLE 6.1  Physiological Changes Induced

BOX 6.3  Conditions That Have Been Shown

Physiological Function

• Angina54,190,191,209,210 • Anxiety51,211,212 • Arthritis38,168,213 • Asthma214–217 • Behavioral problems218 • Claudication, intermittent193 • Common cold219–222 • Cough223 • Depression224,225 • Diabetes (non–insulin-dependent diabetes mellitus)196,197 • Drug dependence51 • Dysmenorrhea226 • Dyspepsia227 • Gastric ulcers228 • Hayfever229,230 • Headaches, temporal and vascular 231–233 • Hypertension234,235 • Labor and postpartum pain236 • Premenstrual syndrome237 • Ménière’s disease238 • Nausea of pregnancy51 • Pain106,239 • Psychoneuroses52,240 • Rhinitis241 • Sleep disturbances242 • Tremor54

by Placebo Heart

Sympathetic stimulation Claudication Opioid dependence Postsurgical trauma Diabetic blood sugar dyscrasias (NIDDM) Gastrointestinal secretion and motility Hypertension Motor dysfunction

Physiological Changes tolerance190,191

Improved exercise Decreased serum lipoproteins192 Improved T waves57 Decreased pulse rate and arterial pressure59 Decreased tremulousness, sweating, and tachycardia51 Increased walking distance193 Addictive drug withdrawal194 Decreased facial swelling195 Lowered fasting blood sugar196,197 Decreased gastric acid secretion198 Changes in gastric motility165,199 Healing of duodenal ulcers200 Lowered blood pressure201–203 Reduced urinary catecholamines204 Improved tremor magnitude205

NIDDM, non–insulin-dependent diabetes mellitus.

The large and ever-growing number of studies on placebos and double-blind research (Box 6.3) supports the following assertion made by Beecher20 30 years ago: Many “effective” drugs have power only a little greater than that of placebo. To separate out even fairly great true effects above those of placebo is manifestly difficult to impossible on the basis of clinical impression. Many a drug has been extolled on the basis of clinical impression when the only power it had was that of a placebo. 

to Respond to Placebo

that in any given situation, responses to a placebo may vary as compared to any other situation and the significance of situations to human subjects cannot be precisely duplicated.51 

Myth 3 “The placebo effect is found only with substances that are inert.” Fact: The placebo phenomenon has been observed across a wide spectrum of medical disciplines including surgery,43 drug therapy,44 and biofeedback.45 

Myth 4 “The patient who responds to placebo therapy can be characterized as someone who is of a typical neurotic disposition.”41 Fact: Although many studies have tried to impute a personality type, disposition,45,46 or certain epidemiological class47 to the patient who responds to placebo, this has yet to be well demonstrated because, in the right circumstances, any person can become a placebo reactor.48,49 After reviewing the bulk of the research on this subject, Bush50 and Wolf and Pinsky51 concluded that the attempts to pigeonhole personalities into a clinical profile ignored the complexity of the human mind. Gliedman et al.52 similarly reported that age, sex, marital status, social class, and intelligence were unimportant factors in determining a patient’s response to placebo. Wolf summarized that attempts to identify placebo reactors need to identify the nature of the symptom being treated, the motivation of the patient and physician, the nature of the test agent, its mode of administration and the life situation of the subject at the time he is tested. The significant point here is not the apparently conflicting findings of investigators with respect to placebo reactors, but rather

PHARMACODYNAMICS The physiological response of the “inert and inactive” placebo extends into the realm of drug pharmacodynamics. Dose–response time curves, cumulative effects (increasing therapeutic efficacy with repeated doses),53 variable strengths of analgesia based on a patient’s drug expectation,54 drug interactions,51,55 and carryover effects46,56 have all been demonstrated. The effects of placebos are so pronounced that some observers have suggested that they can exceed the effects attributable to potent pharmacological agents.51

Packaging and Delivery Several studies found that the effectiveness of placebo therapy depends on the mode of delivery.57 For example, one study found that green tablets improved anxiety and yellow tablets improved depression,58 whereas another study found that blue capsules were more sedative and pink capsules were more stimulating.59 Placebo injections appeared to be more effective than oral administration after oral placebo has failed to relieve the patient’s symptoms.38 

Placebo Interactions Benson60 wrote that the patient’s belief was also a powerful force in determining the level of relief afforded by the placebo. An increase in patient expectation enhances the physician’s ability to elicit a placebo response. Even if patients know that they are receiving placebos, the expectation and relief brought about by the therapeutic interaction

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provide positive results.61 The importance of expectation was further demonstrated by the observation that the greater the stress level of the patient and the greater his or her need for assistance, the greater the effectiveness of placebo.62 This was seen even in patient responses to psychotropic drugs: d-lysergic acid diethylamide tartrate 25 (LSD25) could have no effect if the patient was told that the drug was a placebo.45,63 Patients, such as war heroes, who had severe injuries but did not have great mental suffering attached to their pain needed less pain medication than persons with similar injuries who had pain that engendered anxiety and connoted disaster.64 

PLACEBO HEALING MECHANISMS When animals or humans can react to their own deviations from homeostasis and when these deviations set off restorative processes, therapeutic intervention, including placebo, has an already existing substrate of recovery for exploitation.17 A human being has an intrinsic ability to “self-right”—vis medicatrix naturae (the healing power of nature). This is the keystone of a philosophy that has been held for thousands of years by naturally oriented physicians (see Chapter 5). The concept of a homeostatic, self-regulating mechanism is central to the understanding of basic concepts of physiology: negative feedback loops control virtually all systems of the body. According to Guyton,65 “the body is actually a social order of about 75 trillion cells organized into different functional structures.… [E]ach cell benefits from homeostasis and in turn each cell contributes its share toward the maintenance of homeostasis.” The body can maintain health and reestablish a healthy state after disease by virtue of its inherent vitality. This is part of the definition of a homeostatic mechanism; it has been selected by nature in the same way that organs vital to our survival have been selected. The surviving species are those most fitted and best able to cope with dysfunction. Those organisms that can tolerate the greatest stresses and still maintain normal physiology are the hardiest survivors and ensure the species’ ability to increase the limits of its adaptation. Therefore, given that an organism is self-maintaining when in an environment that it has been selected for, healing happens unaided through simply maintaining an environment that does not obstruct the path of cure. As Norman Cousins66 observed, “without any help, the human body is able to prescribe for itself. It does so because of a healing system that is no less real than the circulatory system, the digestive system, the nervous system, or any of the other systems that define human beings and enable them to function.”

The Role of Emotions Starting in the 1970s and early 1980s, review articles began to examine the effect of the mind on the immune system, emphasizing mechanisms and pathways that gave rise to a new field called psychneuroimmunology.5 Reviews of studies that explored how specific emotions can increase cancer susceptibility,67,68 examined the effect of emotions and recovery from cancer,69 investigated the increased incidence of sudden and rapid death during psychological stress,70 and monitored the changes in immune function during emotional stress71,72 all confirmed that emotions play a powerful role in the prognosis of a patient. Cannon32 and Tregear73 documented dramatic case histories of pioneering anthropologists who witnessed the power of taboos and curses to kill strong, healthy men and women in third-world cultures throughout Africa, South America, and the South Pacific. Tregear73 wrote, “I have seen a strong young man die the same day he was tauped [tabooed]; the victims die under it as though their strength ran out as water.” 

The Vis Medicatrix Naturae The healing process described as vis medicatrix naturae demonstrates the significant power and potential of the self-generated healing capacity. For a physician, there is no more powerful stimulator of this healing mechanism, the placebo effect, than a strong doctor–patient interaction. Just walking through the door of the physician’s office nudges a patient’s internal homeostatic mechanisms into seeking higher levels of health, healing, and adaptation. The placebo effect is a result or effect of the patient’s seeking the assistance of the doctor’s ability to heal and cure. As Benson60 noted, When we dissected the placebo effect a number of years ago, we found three basic components: One, the belief and expectation of the patient; two, the belief and expectation of the physician; and three, the interaction between the physician and the patient. When these are in concert, the placebo effect is operative.… Perhaps nothing is being transmitted from the healer to the patient, but rather it’s the belief the patient has in the healer that’s helpful. 

Conscious Control Over Homeostasis The body has two internal forces to maintain homeostasis: a lower drive and a higher drive. The lower drive is the inherent internal healing mechanism, the vital force, or the primitive life support and repair mechanism that can operate even in a person who is asleep, unconscious, or comatose. The higher drive is the power of the mind and emotions to intervene and affect the course of health and disease by depressing or stimulating internal healing capacities. The effect of this drive can be seen in the clinical observation of patients who move toward spontaneous remission of a life-threatening disease through positive emotional support15,69 and in patients who fail to express emotions compatible with the body’s attempts to survive.69 In any disease process, the consciousness of the patient decides the effectiveness of any therapy. It has been suggested that widely ranging nondrug stimuli have the capacity to modulate human functioning.74 It is emerging in the medical literature that any sensory stimuli or mental activity is able to alter disease progression. This extends to the thoughts and intentions of those connected to the patient. Experiments in remote intention–generated healing and prayer showed that the intention of others was a factor in the homeostatic capabilities of the mind and body. The fact that the homeostatic mechanism can sense and respond to these remote intentions is a reflection of the power of the human mind. Some authors believe that there is a physiological basis for the unlimited possibility of human voluntary control.75 The conclusion that awareness or “mind,” anyone’s mind—the patient, the doctor, or someone who is aware of the patient—can alter the patient’s physiology is a testament to the “holos” concept in different schools of alternative and complementary medicine. This idea flies so deeply in the face of our mechanistic model of medicine, it forces a complete paradigm shift in the conventional social ethos of medical care. The ultimate control of psyche over soma demonstrates the priority of the conscious mind over physiological processes such as immunity and pain control.76 This puts an enormous responsibility on the physician. He or she must take full account of a patient’s mental and emotional states when treating chronic or life-threatening disease.

Physiological Mechanisms Identification of a biochemical mechanism for placebo analgesia has done more to change the image of placebo therapy than any amount of arguing about the importance of beliefs and the mind.77 The mechanisms of the placebo response have been suggested to be a mixture of psychological interactions78 and cognitive states79 mediating physiological responses.19 The psychological components

CHAPTER 6  of the patient’s placebo effect have been shown to include decreased anxiety and increased relaxation,54 conditioning,18 expectation,23 and well-being generated by the establishment of a sound doctor–patient relationship.80,81 Review articles summarized a wide range of receptor-agonist mechanisms driving the neural pathways in different parts of the brain.82 To date, endorphin, dopamine, cholecystokinin, interleukins, growth hormone, and cortisol have been implicated. The physiological mechanisms of the placebo effect were suggested to include chemicals, catalysts, and enzymes. It is believed that steroids, catecholamines,15 the autonomic nervous system,19,83 neuropeptides, and endorphins84 are also involved. These physiological mechanisms interrelate synergistically and are currently being researched within the rapidly developing field of psychoneuroimmunology,7 through which the links between depression, affective disorders, emotions, and the immune system and central nervous system (CNS) are being explored. Susceptibility to depression and sensitivity to pain have now been found to be mediated through neurotransmitters such as catecholamines, serotonin, and dopamine. The current model for explaining the mechanism by which emotions, mood, and psychological stress suppress immune function involves cerebral–hypothalamic and pituitary interaction, which translates stress and anxiety into an autonomic–endocrine response. This response adversely affects the immune function, particularly after chronic stimulation. Stressful stimulation is received in the sensory cortex of the brain and is then referred to the limbic system and the hypothalamus. This interface of higher-brain functions and homeostatic regulating centers provides the communication link between the psyche and soma. According to Rossi,19 “The hypothalamus is thus the major output pathway of the limbic system. It integrates the sensoryperceptual, emotional, and cognitive function of the mind with the biology of the body.” The nerve centers that control both branches of the autonomic nervous system (both parasympathetic and sympathetic), nerve cells that secrete endocrine-releasing factors, and neural pathways that release hormones directly into the posterior pituitary are in the hypothalamus. The corticosteroids and catecholamines from sympathetic stimulation are key factors in the alteration of disease susceptibility in response to stress. Corticosteroids inhibit the function of both macrophages and lymphocytes, as well as lymphocyte proliferation.85 Corticosteroids also cause the thymic and lymphoid atrophy noted by Hans Selye in his experiments on stress-induced immune dysfunction.86 The autonomic release of catecholamines stimulates receptors on the surface of lymphocytes, thereby increasing their maturation rate. When lymphocytes are in a mature state, their ability to kill bacteria and cancer cells and produce interferon seems to become paralyzed.87 Thus a population of mature lymphocytes develops, ready to defend the body from infection and inflammation, yet remains paralyzed until the “red alert” signal of sympathetic fight or flight is turned off, signaling the appropriate time to rest and repair. A number of other peptides, E-type prostaglandins, somatotropin, histamine, insulin, endorphins, antidiuretic hormone, and parathyroid hormone all have receptor sites on lymphocytes and can stimulate the same cyclic adenosine monophosphate–mediated response resulting in lymphocyte maturation and inhibition.85 A study of the effect of catecholamines on the human immune system showed that when a physiological dose of epinephrine was injected into a healthy volunteer, there was an increase in the number of circulating suppressor T lymphocytes and a decrease in the number of circulating helper T lymphocytes (changes similar to those found in acquired immunodeficiency syndrome [AIDS]).85 

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Neurophysiology of Placebo Response Medical research has continued to expand the understanding of the placebo healing response, extending the understanding of the complexity of the brain functions that control healing in the body.88 One review article did an excellent job of summarizing the psychobiological mechanisms involved in the wide array of medical conditions observed in the placebo response literature.2 Imaging techniques such as positron emission tomography and magnetic resonance imaging (MRI) have literally illuminated the areas of the brain involved in generating the placebo effect.89 One fascinating development is the indication that the placebo effect may be especially useful in depression, anxiety, substance abuse, and neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. Research has indicated that the conditioning and anticipation of the patient have a potent effect of stimulating specific brain region activity associated with pain modulation and neurohormonal regulation.

Brain Region Activity Some of the most interesting research on placebos has evolved out of the new MRI technology. This functional MRI (fMRI) can measure blood flow into specific areas of the brain. One study showed that expectation or hope was able to stimulate a certain part of the brain that is activated by pain medications and is associated with pain relief. Placebo analgesia was found to be related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex. It was also associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.90 In another study, researchers found that empathy could activate a portion of the brain. They showed that some of the brain regions involved in feeling physical pain became activated when someone empathized with another’s pain. Using fMRI, study participants were observed when they experienced a painful stimulus, and the results were compared with those elicited when the participants observed their spouses receiving a similar pain stimulus. The bilateral anterior insula, rostral anterior cingulate cortex, brainstem, and cerebellum were activated when participants received pain and also by a signal that a loved one experienced pain.91 A group of researchers at the University of California at Los Angeles, using a new technology called quantitative electroencephalography, showed that “effective” placebo treatment induced changes in brain function that were different from those associated with antidepressant medication. Placebo responders (those who showed a response to placebo) showed a significant increase in prefrontal activity starting early in treatment that was not seen in medication responders or in participants who showed no response to medication or placebo. Because a high percentage of antidepressant medication represents the placebo effect, it is important to be able to predict who will be placebo responders.92 

Placebo and Stress Physiology The stress “letdown” of a patient in the therapeutic environment is one of the mechanisms that produces the placebo effect. It results from the patient’s perception that a transition from a stressful situation to a nonstressful situation has occurred. Mowrer87 observed that with a decrease in anxiety, there is a concomitant increase in hope, signifying that the period of suffering is over. Certain familiar images and signals, such as white coats, syringes, behavioral procedures, and clinical protocol, create a conditioned response—relief now that help has arrived. Evans and Hoyle54 similarly observed that “the reduction of fear through the shared expectations that the doctor’s medicine will work—even if unknown to the patient it is placebo—mediates powerful therapeutic effects.”

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The placebo effect in the clinical environment transforms the emotional and mental stress of the patient. These effects, also observed and described by Franz Alexander,16 Hans Selye,86 George Solomon,93 and Walter Cannon,94 allow the patient to escape the “fight-or-flight” response that can cause and maintain the state of illness. 

Physiological and Psychological Stress Selye86 demonstrated that physiological stress can have a dramatic effect on the immune and endocrine systems of the body. Laudenslager95 went on to show that it is not just stress that creates these physiological changes; the perception that stress is “inescapable” is critical to the response. More recently, studies on the effects of psychological stress demonstrated significant changes in immune capability. Maladjustment to “life-change stress” correlated with reduced activity of natural killer cells,93 decreased T- and B-cell responsivity,71 and diminished lymphocyte cytotoxicity.96 For example, Riley97 observed increased tumor activity in a controlled stress environment and concluded: Emotional, psychosocial, or anxiety-stimulated stress produces increased plasma concentrations of adrenaline, corticosteroids and other hormones through well-known neuroendocrine pathways. A direct consequence of these increased corticoid concentrations is the injury to elements of the immunologic apparatus, which may leave the subject vulnerable to the action of the latent oncogenic viruses, newly transformed cancer cells, or other incipient pathologic processes that are normally held in check by an intact immune system. The damage to the immune system by stress, mediated through the hypothalamic–pituitary axis, has been shown to be due to the increase in serum levels of cortisol. In one study, elderly caregivers were shown to have higher cortisol levels and poor antibody response to influenza vaccine.98 The effect of cortisol on immune and other regulatory functions, such as the regulation of blood sugar, dehydroepiandrosterone (DHEA), insulin, testosterone, and bone resorption, flag it as having highly destructive potential. Anxiety, depression, heart disease, AIDS, and osteoporosis have all been linked with elevated cortisol levels. DHEA, another adrenal hormone, is also modulated by stress physiology, although it seems to have the opposite effect of cortisol. High levels of DHEA seem to protect the body from the damaging effects of elevated cortisol. Ratios of DHEA to cortisol are highly predictive of the individual’s ability to tolerate stress.99 Current reviews of the literature relating psychological stress and immune dysfunction support the hypothesis that homeostatic immune mechanisms, both humoral and cellular, are significantly impaired by both natural and experimental stress.5,61,84,100 Hypertension,101 common colds,102 coronary artery disease,103 and myocardial ischemia104 were linked to adverse stress physiology. Stress even has the ability to increase the permeability of the blood–brain barrier.105 The implications of stress-related alterations in the blood–brain barrier expose important insights into enigmatic diseases like chronic fatigue syndrome and stress-induced neurological disorders. 

Endorphins, Hormones, and Neuropeptides …one rapidly activated psychoneuroendocrine mechanism through which a placebo stimulus may reduce both depression and pain is produced by stimulating the endorphin system.18 Research on endorphins is a relatively new area of study in the field of psychoneuroimmunology. Original research by Levine et al.106 suggested that the pain relief noted in placebo studies could be explained by the simple mechanism of endorphin-mediated actions. The original emphasis on endorphins and enkephalins was plausible, considering their known modulation of pain and mood functions. This

TABLE 6.2  Effects of Endorphins on the

Immune System

Immune System Function

Endorphin Effect(S)

Lymphocyte production Chemotaxis T-cell sensitivity to prostaglandin E2 Antibody production Complement T-cell proliferation Natural killer cell function B-cell differentiation

Increased and decreased Increased Increased Increased and decreased Binding of fractions C5B-C9 Modulation of Modulation of Modulation of

position was further supported by later observations that depression increased chronic clinical pain107 and that decreased activity in endogenous opioids may be part of the pathophysiology of depression.108 With the information that placebo can stimulate endorphins, Levine et al.106 believed that an explanation for the action of placebos had finally been found. Furthermore, research showed that an endorphin-mediated, pain-suppressant placebo effect could be abolished with the use of Naloxone, an opioid antagonist.109 The same authors went on to further show that endorphin-mediated placebo effects penetrated other physiological systems besides pain management.110 However, this hypothesis failed to account for the broad spectrum of placebo effects as well as for the fact that the analgesia associated with hypnosis was not affected by an opioid antagonist.111,112 It is important to note that later literature suggested that Levine et al.106 were not entirely wrong in implicating the role of endorphins in the placebo mechanism; rather, these researchers were right for the wrong reason. Endorphins are mainly derived from three precursor proteins (by separate biochemical processes).113 These opioid peptides are released from central and peripheral areas in response to pain, stress, and emotions and perform many physiological functions, of which analgesia is but one.114 However, it is becoming evident that the boundaries between the CNS and the immune system are not as clear as once thought. The several known effects of endorphins on immune system function are listed in Table 6.2.115 When the functions of neurotransmitters such as endorphins are found to have such an intimate relationship with immune integrity, the paradigm of a body with functions performed independently by its parts—a Newtonian type of thinking—begins to lose credibility. To further blur the already hazy distinction between the CNS and the immune system, research demonstrated that endorphins and peptide hormones, such as adrenocorticotropic hormone, thyroid-stimulating hormone, human chorionic gonadotropin, and luteinizing hormone, are produced by lymphocytes.115 It is clear that the demarcation between the CNS and the immune system is impossible to distinguish. The brain and the immune system are the only tissues in the body that have a memory, and the level of communication between the two argues a taxonomy that identifies them as one. Evidence of the innervation of the thymus gland, bone marrow, spleen, and lymph nodes supports the finding that the immune system is subject to efferent CNS information.115 In addition, studies demonstrating the atrophy of the thymus and lymphatic tissues in the absence of growth hormone,116 adrenocorticotropic hormone, and increased steroid production by adrenal cells after interferon stimulation indicate that “in the future it will be difficult to distinguish the receptors and signals that are used within and between the neuroendocrine and immune system.”115 

CHAPTER 6 

BOX 6.4  Six Principles of Optimizing

Placebo Response in Clinical Practice

• Prima non nocerum: Prioritize a hierarchy of therapeutic interventions. • Tollem causum: Remove the obstacles. • Support the therapeutic relationship. • Enhance positive emotional states. • Implement therapeutic conditioning or learning. • Use altered states of consciousness.

CLINICAL APPLICATION Whether a clinician intends to initiate a placebo effect in a clinical setting or not, the mind of the patient will initiate some subliminal healing effects according to the patient’s hope, expectation, conditioning, anxiety reduction, and meaning around the disease and treatment. A recent article in Lancet2 on placebos concluded, “Any ethical assessment of efforts to promote placebo effects in clinical practice first requires knowledge as to the clinical relevance and importance of placebo effects.” A physician with an interest in psychopharmacological treatment, which can be expensive, elaborate, detailed, time consuming, esoteric, and dangerous, usually has considerable knowledge about such treatment. He or she is interested in the symptoms of the patient and the differential response to various drugs and is careful to observe side effects, which may be dangerous. The physician may encourage the patient to call at any time if side effects develop.26 The application of the placebo phenomenon in clinical practice should not be a vague attempt to replace the skill of the medically trained physician with obscure “hand waving,” incantations, and inert lactose pills. In primary care and specialty clinical practice, the physician’s intent should be to optimize patient care by engaging restorative defense mechanisms. To effectively apply current placebo research, the physician must understand several principles (listed in Box 6.4 and discussed here).

Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care Prima non nocerum is the Hippocratic injunction dictating that a physician care for the patient so that self-healing mechanisms can engage. This ancient phrase means “Do not disturb the organism’s ability to heal itself.” The body must be given the full range of possibilities in allowing the power of homeostasis, vis medicatrix naturae, to have its optimum capability. “Doing no harm” means that a patient is supplied with the level of medical intervention that is appropriate to his or her ability to maintain life support. The job of the physician is to determine when homeostasis or the defense mechanism has lost the ability to respond to disease. Acute traumatic swelling and inflammation and shock are examples of the human defense mechanism responding in a way that threatens the health of the organism. It is most interesting that the organism would make choices, as in shock and inflammation, that could kill it. To practice the principle of prima non nocerum, a physician must learn when to act and when to let the body heal itself. This is the highest art of medicine; each case and situation is different, and it is up to the physician to interpret the needs of the moment. By implication, the physician who seeks to apply this principle understands the principles of physiology on which human life depends for homeostasis. Prima non nocerum does not necessarily mean that a physician withholds invasive therapy: it is the physician’s responsibility to determine when the body is unable to reestablish homeostasis and therapy

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is indicated. If an arm must be severed to save the patient’s life, there is no violation of prima non nocerum. However, to enhance the principle of prima non nocerum, a physician sometimes must withhold therapies and must be content to leave the patient to self-heal. Hippocrates understood the wisdom of letting the body heal on its own, which is implicit in the injunction to “do no harm.” The following account of the treatment of Charles II of England is a case in point117: A pint of blood was extracted from his right arm and a half pint from his left shoulder, followed by an emetic, two physics, and an enema comprised of fifteen substances; the royal head was shaved and a blister raised; then sneezing powder, more emetics, and bleeding, soothing potions, a plaster of pitch and pigeon dung on his feet, poisons containing ten different substances, chiefly herbs, finally forty drops of extract of human skull and an application of bezoar stone; after which his majesty died. When this treatment is compared with modern procedures, such as mammary artery ligation for the relief of angina—a procedure that has no more benefit than sham artery ligation—it appears that physicians continued throughout the centuries to rely on the placebo effect for the care and cure of their patients. Recently, the invasive standard-of-care procedure percutaneous coronary intervention (PCI) of angioplasty and placing coronary stents was shown to be no better than placebo for stable angina. Missing from the medical community discussion on this study was the remarkable fact that some individuals who underwent the sham “placebo” PCI procedure had results that demonstrated that the placebo effect can affect cardiac perfusion.118 Our medical culture has very little interest in exploring the physiological limits of self-healing. Because this effect plays such an important role in health care, simple, noninvasive, and effective treatments should be the goal of all therapeutic approaches. Robert Burton119 wrote in 1628, “an empiric oftentimes, and a silly chirurgeon, doth more strange cures than a rational physician… because the patient puts confidence in him.” The rational physician will also recognize that healing and curing are not necessarily the same. If a patient is helped in any way by the doctor, with or without the use of a placebo, the path of cure has been assisted, although the specific disease may not have responded. Not all patients can be cured, but most patients can be helped. 

Tollem Causum: Remove the Cause of Disease Tollem causum is the principle that seeks to remove the obstacles to cure. The forces “inhibiting the floodgates of health from opening” must be removed for the full force of the patient’s beliefs to effect the path of cure. This concept is fundamental to the philosophy of naturopathic medicine, with its strong emphasis on diet, detoxification, and a pattern of living that is consistent and compatible with the context in which humans evolved. Obstacles to cure block the self-healing capacity of the organism. Contamination with heavy metals and xenobiotics (see Chapter 35), focal infections, electromagnetic pollution, scar tissue, genetic metabolic abnormalities, and parenchymal organ damage defeat the best therapeutic intentions and must be addressed. The patient’s habitat is an important aspect of the therapeutic protocol, not only in the diagnosis and care of internal mental and physiological dysfunction but also in determining which environmental factors may be contributing to dysfunction and disease. These factors might include diet, lifestyle, and living environment. It is of the utmost importance to remove a patient from surroundings that are associated with illness or to assist the patient in creating an environment more conducive to health.

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Factors that provide conditioning that reinforces the disease process can be associated directly or indirectly with one’s environment. For example, if animals are returned to situations where their experimental neuroses were induced, their pathological behavior reactivates.120 When a patient leaves the offending environment to receive treatment from a physician, the prognosis is correspondingly more favorable.17 The physician has the added advantage of a patient’s heightened expectation during an office visit; a patient’s positive associations with the “healing” environment increase his or her receptivity to treatment.121 If the home or work environment is a source of “disease” and an obstacle to cure, providing an alternative environment may be a most helpful way to remove the obstacles to cure. 

Support the Therapeutic Relationship Confidence should surround all aspects of the therapeutic interaction. The patient must have confidence in the doctor’s ability to assist a cure; the doctor must have confidence in the efficacy of his or her therapy122; and there must be an understanding or relationship between the doctor and patient that is mutually conducive to respect, trust, and compassion. The quality of the doctor–patient relationship is paramount. The therapeutic approach to a patient that optimizes the confidence of the patient in the skill of the doctor stimulates the inherent self-regulating healing mechanisms by relaxing the anxiety the patient has about the illness. Anxiety is a well-known immunosuppressant and aggravates the body’s defense mechanisms. An optimum therapeutic relationship, when combined with the clinical skill to remove the cause of homeostatic dysfunction, is the height of therapeutic acumen. As Lewith123 so accurately stated, “The general practitioner may therefore wish to employ all his knowledge, enthusiasm, consultation technique and sympathy, to create the best possible atmosphere in which to elicit a placebo response from the patient.” Current research on factors contributing to the genesis of the placebo effect consistently document the importance of the doctor– patient relationship.124–126 The healing power of the therapeutic interaction has been demonstrated by the commencement of the placebo effect even before the actual administration of the pill.127 The physician facilitates the cultivation of a sound relationship by developing good communication skills. The art of the bedside manner has been recognized throughout history as the primary skill a successful physician needs.128 The history of medicine is as much a history of the relationship between doctor and patient as the evolution of medical technology and techniques. Through centuries in which doctors were doing more harm than good, little more than the esteem of their clientele sustained the medical profession. But however little real help the doctor had to offer, it was to him that people turned when illness struck.129 Bedside manner has been found in clinical studies to entirely alter the course of double-blind studies, and the quality of a therapeutic encounter has been found to facilitate or disrupt the efficacy of a treatment.130 Listening to the patient,130 the verbal and nonverbal communication of the physician, the amount of time spent with the patient,131 patient education,132 the demeanor of the physician,133, and interview skills131 have been suggested as factors and components of effective physician communication skills. Communication between the doctor and patient is not simply a process of one party talking and the other side listening. Deep communication between both sides is a process of “interbrain” synchronization—literally, the brain waves of two people talking begin to match each other, as described in a research study by researchers at the Basque research center BCBL.134 This synchronization or lack of it may be an important aspect of interpersonal communication. The examination of placebo dynamics uncovers the complexity, depth, and importance of the doctor–patient relationship.

Many factors may be responsible for the varying therapeutic effects of the physician–patient relationship. An open-minded investigation of this relationship brings us, incredibly, to the possibility of brain-tobrain coupling, an interconnected matrix of the mind of the healer and the healed.135 Learning to “listen” or synchronize with the patient you are communicating with ensures optimum transfer of information, hope, empathy, and a host of essential dynamics between doctor and patient. Touch is an important form of communication and is sometimes forgotten as a key aspect of the doctor–patient relationship. Highly skilled clinicians with many years of experience, such as the now deceased Dr. John Bastyr (whose remarkable healing abilities inspired the founding of Bastyr University by those privileged to have been his students), frequently impressed upon clinicians the importance of always using diagnostic and therapeutic touch during a patient visit. The doctor’s touch can be diagnostic, therapeutic, and, perhaps most important, a means of communicating that he or she is deeply attuned to the problems, needs, and fears of the patient.133 Touch can heal by increasing tissue mobility and fluid exchange, as in massage, or by relieving pain, as demonstrated by research on healers who use their hands.136 Touch has also been documented in well-designed double-blind research to extend an unusual healing power that can be transmitted through the hands to plants and animals.137 Among other methods of enhancing confidence between the doctor and patient, the setting in which a doctor provides therapy to a patient also determines its effectiveness. The doctor’s office setting is very important for optimum and effective treatment: tools and support systems are more accessible, and a heightened patient response results from seeking out the “healing” environment. In a clinical trial with hypertensive patients, placebo alone was not as effective as when it was administered in conjunction with hospitalization. The visit to the physician represents a search for changes that cannot be found through “self-care” or over-the-counter medicines. According to Frank138: In short, it appeared that the placebo situation relieved chiefly anxiety and depression, that the degree of relief was unrelated to personality and autonomic measures, and that the patients who responded strongly to a placebo at one time might not at another. In conjunction, these results suggest that the extent of responsiveness to a placebo depends on the interaction of the patient’s state at a particular time with certain properties of the situation. The finding that administration of tests and questionnaires seemed to have at least as beneficial an effect as had the pill implies that any interaction between patient and situation that heightens expectations of help may lead to symptom reduction and improvement in mood. The aspects of the situation producing this effect include not only presentation of a symbol of the physician’s healing powers (a pill), but any attention and interest shown by professional personnel. This phenomenon was also observed in industry and termed the Hawthorne effect. As a direct result of the greater attention factory workers received during investigation, the quality of their work improved.139 In conclusion, the importance of a doctor–patient relationship and the confidence that it engenders shows that all human beings need to share their feelings and experience the therapeutic benefits of touch: the doctor–patient relationship provides an ideal way to meet these fundamental needs. 

Enhance Positive Emotional States Love in all its subtleties is nothing more, and nothing less, than … the psychical convergence of the universe upon itself. —Pierre Teilhard de Chardin, The Phenomenon of Man

CHAPTER 6  For optimum enhancement of the psychoneuroimmune system, the physician must assist the patient in developing practices that amplify positive emotional states and reduce a negative emotional state. A negative mental state (anxiety, stress, panic, anger, depression, neurotic behavior, self-deprecation, self-destructive feelings and tendencies, and a weak will to live) hinders the ideal functioning of the psychoneuroimmune endocrine axis, disrupting homeostasis. Engle140 termed this the giving-up/given-up complex: Study of the life settings in which patients fall ill reveals that illness is commonly preceded by a period of psychological disturbance, during which the individual feels unable to cope. This has been designated the giving-up/given-up complex and has the following five characteristics: a feeling of giving up, experienced as helplessness or hopelessness; a depreciated image of the self; a sense of loss of gratification from relationships or roles in life; a feeling of disruption of the sense of continuity between past, present, and future; and a reactivation of earlier periods of giving-up. It is proposed that this state reflects the temporary failure of the mental coping mechanisms with a consequent activation of neurally regulated biologic emergency patterns. Changes in body economy so evoked may alter the organism’s capability to deal with concurrent pathogenic processes, permitting disease to develop. The importance of reducing negative mental states in acute and chronic conditions has been discussed extensively.70 Acute psychological stress is documented to cause various forms of cardiopulmonary dysfunction and even death.61 Chronic mental and emotional strain causes a breakdown of the immune system and can lead to disease. The homeostatic processes become overwhelmed by autoimmune, microbial, or neoplastic invasion. Major writers on the subject of acute and chronic stress emphasize the high priority of managing the physiologically and immunologically destructive effects of the human body’s response to stress. Pelletier141 listed hypertension, arteriosclerosis, migraine headache, cancer, chronic bronchitis, emphysema, asthma, and arthritis as disease processes that are caused or exacerbated by stress physiology. A study researching the relationship between resistance to streptococcal infections in families and stress load in the family found a positive correlation.142 Another study on the psychosomatic susceptibility to infectious mononucleosis found that two psychosocial factors, high motivation and poor academic performance, significantly increased the risk of “disease” infection.143 In still another, anticipation of mood and menstrual discomfort were positively correlated and manipulated, thereby supporting the suspicion that expectations act as a determinant of mood.144 The conclusion that there is no acute, chronic, or degenerative disease that is not affected by a patient’s mental and emotional state must be drawn from the pervasive immunoendocrine effects generated by the mind and emotions. Wolf145 and Cousins146 wrote of the power of panic as a factor in myocardial infarction; Marbach et al.107 described depression as a component in myofascial pain dysfunction; and Shekelle et al.147 noted, in a 17-year follow-up study, a twofold increase in the incidence of cancer in depressed patients. The clinical scenarios these observers described imply that the placebo effect can control the onset and advance of a disease by shutting down the destructive thoughts, images, and feelings that mediate stress. Enhancing positive emotions is the corollary of controlling the damaging effects of negative mental and emotional states. Laughter,23 hope,148 acceptance,64 and the reduction of suffering149 have been shown to speed the course of healing and reduce the level of pain and distress reported by patients. Although pain is sometimes the only

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language nature can use to adequately communicate to the patient that something is in need of healing, “the relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the sick.”149 Acceptance has been observed to be a key factor that assists patients in better understanding their pain.64 Acceptance does not mean complacency in the face of disease but a rational understanding of the situation and the limitations that can sometimes accompany a disease process. The importance of cultivating hope in a patient also cannot be underestimated.150 The fact that a patient seeks the help of a physician or “caregiver” already implies a substrate of hope and is a signal that the patient can visualize the potential for recovery. The treatment needs to merely stimulate this willingness to envision a future of health. Hope is an embodiment of the patient’s and the doctor’s ability to visualize an image of healing and recovery. This process is a recurrent theme in imagery therapy,151 visualization therapy,152 therapeutic touch,153 and psychic healing.154 Hope is both an active and a passive placebo. The passive hope placebo is that which is brought with the patient as the act of seeking help generates a level of unspoken faith in an image or potential for cure. The active hope placebo is generated by the physician, who consciously instills a vision or image of cure in the patient as an adjunct to therapy. Frank138 performed a double-blind study in which patients were divided into control and induction groups. The induction group was led through a process whereby their hope was strengthened to conform with the expectations of the therapist138: It introduces some perceptual clarity into the process of treatment; and to the extent that all our therapists adhered roughly to the insight model of therapy, it helped to bring the patient’s expectations in line with what actually occurred in treatment, and also helped him behave in accordance with the therapist’s expectations of a good patient. The induction group was actually being consciously strengthened to a level of optimal response but was not being led into false expectations.155 This type of patient education or active placebo is a necessary and useful tool for framing and directing a positive outlook and prognosis. If a patient can conceive of a state of wellness, then that state of wellness can be achieved. It is the job and domain of the physician to discover those images, emotions, and perceptions that reside in the conscious and subconscious mind of the patient that block the image of a positive state of health. He or she must actively work to control these with the same level of intent as with any presenting gross complaint or physiological dysfunction. Finding these dysfunctional mental substrates and working with the patient to try to change them is fundamental to treating the true cause of disease (see earlier discussion of tollem causum). Research demonstrated the importance of positive and negative thinking in heart disease and cancer, the two areas of disease that cause the highest death rate. Doctors’ health care management protocols should reflect this research in the same way that attention to a proper diet is part of a management approach to high serum cholesterol. It is now clearly established, for instance, that even low levels of stress trigger the onset of myocardial ischemia.156 We also know from the work of Steven Greer157 and David Spiegel158 that attitude and emotional exploration are critical to breast cancer survival. Knowing these scientific facts, all doctors must have strategies for helping their patients explore the areas of stress management, group therapy and support groups, and skills in building positive attitudes. 

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Implement Therapeutic Conditioning or Learning Those who remain at least dimly aware that everything they say or do to a patient conveys a major or minor, positive or negative, and helpful or harmful psychological impact are likely to be more effective physicians.159 Conditioning of the mind has been suggested as a mechanism by which the placebo effect becomes a learned response.17,19,138 The future of the therapeutic application of placebo will probably hinge primarily on the use of conditioning. A doctor who can understand this will pay close attention to the stimuli of his or her patients and modify these stimuli in a scientific way to help treat immune-related and neurologically related diseases. Modern psychology acknowledges two models of conditioning or reinforcement of learning behavior, operant and classical. Operant conditioning is a behavior response that theoretically occurs in the presence of some stimulus that is a positive reinforcement; for example, a rat will learn to press a conditioning bar if a food pellet is dispensed as a result. Classical conditioning is a behavior response created by the simultaneous pairing of unconditioned and conditioned stimuli before an evoked response. This is best illustrated by the experiments of Pavlov and his “salivating dog.” In Pavlov’s experiment with the conditioning of a dog’s salivary response to the ringing of a bell, the bell ring is the conditioned stimuli, and the food is the unconditioned stimuli. The salivation is the unconditioned response to the food that becomes the conditioned response. When the dog finally associates the bell ring with the food, the ringing alone causes salivation, the conditioned response. The principle of classical conditioning has far-reaching implications for the diagnosis and treatment of disease because of the pervasive and permeating implications that conditioning has in all the sensory stimuli of daily existence, in sickness and in health: “Pavlov’s teachings, concepts and basic notions afford the real and ultimately scientific basis for the recognition of the potentialities of medical science attacking diseases from both the psychic and somatic sides.”160 For the purposes of this discussion, one must recognize that classical conditioning happens randomly in our environment and is closely linked to health and healing phenomena. Subconsciously, we note random events and associate them with previous events and observations, independent of an intended learning behavior. Operant conditioning happens in the context of reward, and classical conditioning happens in the context of associated stimuli. There is a much greater predominance and range of associated stimuli for classical conditioning than for operant conditioning for the genesis of the placebo effect. This is because the operant depends on reward, although operant conditioning can happen in the medical model: “Pain-killing drugs that I have taken in the past kill pain; therefore this capsule, which is a painkiller, will kill my pain.” Gliedman et al.17 noted that drugs that affect the CNS are readily conditioned, whereas drugs that affect the peripheral nervous system and are secretory stimulators (e.g., atropine and pilocarpine) do not result in the establishment of a conditioned response. The primary importance of psychological states to CNS excitation demonstrates that the pivotal loci of command for conditioning reside within the hypothalamus and the limbic system. Therefore a doctor who can induce a state of central excitation in the patient can encourage and condition the patient to make those changes that are deemed necessary for the recovery of health. The conditioning of a patient to a placebo response is modified by learning stimuli associated with the illness, the stimuli of the doctor and the therapeutic setting, the stimuli of the therapy, previous health, medical therapy, and authority-related experiences.161 The way that all

of these factors interact in the psyche of the patient determines the nature of the placebo response that is achieved. Satiation obscures the conditioned response, whereas situations of increased stress seem to potentiate the responsiveness of the placebo effect.64 The placebo effect, conditioning, and learning may therefore be subject to the nature of central excitatory states as well as levels of stress and distress. The physiological breadth of the placebo response in humans can now be understood in terms of the variety of interactions and effects that drugs, therapeutic procedures, and sensory phenomena of the medical environment have on the psychosomatic matrix of a patient’s consciousness. Rossi19 noted that this complicated web of sensory processing reveals how any facet of therapy “that alters any aspect of the body’s sensory, perceptual or physiologic responsiveness on any level can disrupt the more or less fragile state-dependant encoding of symptoms and thereby evoke a ‘nonspecific’ but real healing effect that we call the placebo response.” The scientific basis of therapeutic applications of psychoneuroimmunology is based on classical conditioning. Ader and Cohen162 performed research to show that the immune system could be conditioned for therapeutic purposes. They conditioned immunosuppression in rats by injecting them with a conditioned stimulus of cyclophosphamide (a potent immunosuppressing agent) while feeding them a saccharine solution as an unconditioned stimulus.162 The idea of conditioning for immunomodulation in human patients is therefore a promising therapeutic modality. Applying conditioning techniques for the treatment of systemic lupus erythematosus involving a dosage that normally had minimal results resulted in a delay in the development of the disease.163 To fully account for the extent of previous and future conditioning in a patient, the physician must take a complete and exhaustive history to explore the influences of family, work, accidents, emotional predispositions, medical history, and neutral stimuli as contributing factors during the onset of an illness. Lifestyle and emotional, behavioral, or physiological factors might contribute to maintaining the state-dependent learning pattern of disease and dysfunction or give clues to a successful therapeutic intervention. A good example of this is the demonstration by Batterman and Lower164 of increased analgesic effectiveness based on similar previous therapy. A physician who knows which therapies succeeded and which failed can take advantage of the patient’s conditioning and encourage biochemical pathways that the body has learned. Drug or therapeutic interventions are not procedures that can be predicted in the same way that in vivo experimental results can. The variables involved in human responses to therapy are clearly underestimated in the current rush of research-oriented therapeutic evaluation.165 Therefore a patient who has been treated by a number of physicians or practitioners for a complaint and has received no results or relief has been conditioned to believe that consultation and treatment by a physician will provide no positive changes. When the patient visits the next practitioner, even if this practitioner can offer a diagnosis and treatment that are correct answers to the long-sought cure, there are very real patient conditioning factors that must still be considered. Consider the case of a young woman who underwent treatment for breast cancer and the clinical course of the ensuing metastases. Each time she had a positive response to therapy, she experienced a subsequent remanifestation of the cancer. The result of this conditioning was that she came to equate each new course of chemotherapy as a herald of some new manifestation: she “was torn between a desire to live and the fear that allowing hope to emerge again would merely expose her to misery if the treatment failed.”166

CHAPTER 6  The parameters of conditioning in a clinical setting extend to all aspects of the patient’s sensory perceptions. Consciously or unconsciously, the physician provides an environment for patient learning. Lipkin167 pointed out that every drug, every apparatus, every injection, and every piece of information or advice carries a suggestion of help and hope, regardless of the physiological effects that may accompany it. The physician must realize that patients are taking in all the information about the surroundings, interactions, and therapy and are making associations that can potentially affect the course of their responsiveness to therapy. Mowrer86 observed that the “safety signals” of syringes, laboratory coats, and behavioral procedures were all retained in the patient’s psyche for future association. A physician can skillfully take advantage of these signals by encouraging and cultivating response generalization or by associating previous therapeutic situations with subsequent treatments by means of unconditioned stimuli, such as office music, odors, and images. Giving patients some sort of unconditioned stimulus that can be taken home allows them to associate with the conditioned response, eliciting the memory of the therapeutic interaction while patients are away from the doctor’s office. These unconditioned stimuli or placebos can be given in multiples at one time81; changed for more powerful stimuli168; and delivered at the end of an induction, suggestion, or imagery procedure. They should not be limited to pills or other apparent medicaments and should extend to sounds, smells, visualizations, and feelings. It should be remembered that therapeutic conditioning depends on a perceived physiological shift or change in the patient as described in the theory and research of biofeedback.169 This shift can be experienced as a sense of relaxation, increased warmth or circulation, altered autonomic tone, or a change in some sensory perception. Patients know immediately when there is no change in their disease or dysfunction after they have been given placebo.170 Therefore some patients need a more active form of therapeutic management that allows for some level of perceived change. Ideally this perception would be a sense of being free from pain or alteration from a state of abnormal physiological function to a state of improved physiological function. Acupuncture, spinal manipulation, drug therapy, physiotherapy, hydrotherapy, and surgery are all therapies that can create an immediate biochemical effect that is perceived by the patient. The optimum model to apply to the concept of conditioning therapy and the selection of an appropriate therapy or modality was proposed by Greene and Laskin171 in their evaluation of myofascial pain dysfunction. During an 11-year follow-up study of patients with myofascial pain dysfunction, these researchers concluded that when comparing the effectiveness of a wide variety of reversible and nonreversible (surgical) therapies, conservative and reversible therapies were the most important and appropriate treatment factors for the patient’s health and well-being. Focusing on patient communication, educating patients about the reversibility of the condition and the nature of muscle dysfunction as it relates to stress–pain–spasm, developing a therapeutic strategy based on increasing patient awareness and self-management skills, and selecting a flexible treatment strategy were all found to be essential for achieving a good initial response that could lead to long-term wellness. Greene and Laskin171 believe that the specifics as to which therapy is most indicated are not as important as the need to focus on the nature of presenting musculoskeletal problems and the factors and complexity of the treatment environment. The routine use of active pharmacological substances reinforces the relationship between conditioned and unconditioned stimuli. However, the routine use of unconditioned stimuli in the absence of a conditioned response weakens the therapeutic efficacy of the practitioner and has been described as “placebo sag.”18 Therefore the

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learning of a conditioned response from unconditioned stimuli could diminish if the conditioned stimuli fail to produce an adequate or reliable conditioned response. Without the intermittent demonstration of active strength, the placebo effect will get weaker and weaker. The implications of placebo sag for practitioners of alternative medicine, who try to work with the body’s own defense mechanisms without overwhelming medical intervention, are that periodic use of perceptually active therapy is needed to support a patient who is not able to respond or responds too slowly to a gentler therapeutic nudge. In this case the physician must recondition the vital force to open a path to homeostasis. In a sense, this may be a paradigm of the therapeutic situation, in which changes toward health are induced in the patient by a doctor who is able to cultivate a basic state of arousal, presumably central in nature. This state of arousal causes the patient to become accessible to the doctor’s expectations of the patient.17 The typical placebo burst, in which a therapy is initially effective after a short period but then wanes, is now understood in terms of the placebo sag from a lack of effective unconditioned stimuli to maintain the conditioned framework.168 Physicians who lack the ability to extract themselves from a series of unsuccessful therapies risk eventual placebo sag18: [T]herapists who primarily use their active strengths (or unconditioned stimuli) paradoxically will get stronger placebo effects than quacks, will enjoy escalating credibility, and will seem as miracle men—when in fact perhaps only half their miracles can be traced to their active ingredients while the other half is a function of the anticipatory (or conditioned) response elicited by their conditioned features. Because the visit to a physician is often initiated by the physical pain of the patient, it stands to reason that skillful pain management is a high priority in establishing a therapeutic conditioned response. Pain management by hypnosis, transcutaneous electrical nerve stimulation, therapeutic touch, direct or indirect manipulation, imagery, acupuncture, meditation,172 and an understanding that aims to elicit the nature of suffering166 can all be valuable therapeutic adjuncts to establishing a therapeutic environment that conditions the patient for the full potentiation of his or her healing capabilities. (See Chapter 42 for a full discussion of these techniques.) With the recent development of standardization of, research into, and concentration of the active components of plant medicines, vitamins, and biochemical precursors, naturopathic medicine and other forms of alternative medicine stand on a stronger therapeutic base because of an ever-growing verification of the pharmaceutical and therapeutic armamentarium. These therapeutic modalities are characterized by safe yet physiologically active substances and procedures; therefore they provide some defense against placebo sag. 

Use Altered States of Consciousness Since ancient times, aboriginal humans have recognized the tremendous therapeutic power that lies dormant in the subconscious mind. For thousands of years, shamans and medicine men have used trance states to engage the most subtle aspects of the patient’s subconscious to affect factors in disease pathogenesis and prognosis.173 In modern medicine, it has been documented that shamanistic healing involving altered states can offer dramatic “spontaneous remissions33;” the mechanisms of this process have been explored in the theory and application of hypnosis.4,76 Most currently accepted techniques employed to trigger the subconscious to effect positive changes in somatic or psychic health involve hypnosis. The placebo effect has been linked with hypnosis, or

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“low arousal states,” which are therefore believed to be critical factors in the evaluation of the mechanisms and perimeters of placebo.160 A review of the literature documenting the potency of hypnosis and the observed results of placebo clearly demonstrated that these two areas yielded remarkably similar clinical results. The inquiry into hypnosis grew out of the simple intent to validate the effectiveness of the mind in healing processes, whereas most placebo literature grew out of the intent to demonstrate a certain percentage of chance, fluke, spontaneous remission, or psychosomatic illness as a factor to be ruled out in the delivery of intelligent, scientific health care. Using these antiquated definitions of placebo and hypnosis, one is led to believe that hypnosis describes a process of healing based on the skillful guidance of a qualified practitioner and that placebo describes a process based on chance, regardless of the professional circumstances. On closer inspection, the distinction between the two blurs: they appear to be much the same process. Illness, healing, and health states shift constantly in the homeostatic system, a system that is affected by stimuli received through the different levels of awareness and can be accessed, investigated, and modified by a variety of techniques. These include placebo, hypnosis, and induced altered states of consciousness. Rossi19 noted that because memory depends on and is limited to the level of awareness in which the memory was acquired, it is “state-bound information”: State dependent memory, learning, and behavior phenomena are the missing link in all previous theories of mind body relationships.… The major thrust of these hypotheses is that mind-body information and state-dependent memory, learning and behavior mediated by the limbic-hypothalamic system, are the two fundamental processes of mind-body communication and healing.… The new approach to mind-body healing and therapeutic hypnosis may be conceptualized as processes of accessing and utilizing state-dependent memory, learning and behavior systems that encode symptoms and problems and then reframing them for more integrated levels of adaptation and development. Some psychosomatic phenomena are coded into the behavior of an individual through state-induced patterning. Until the patient can access the state in which somatic complaints are induced, possibly through hypnosis or other methods that break the sympathetic dominance of “encoded” shock,174 the psyche cannot clear them from the soma19: A person in a traumatic car accident experiences an intense rush of the alarm reaction hormones. His detailed memories of the accident are intertwined with the complex psychophysiological state associated with these hormones. When he returns to his usual or “normal” psychophysiological states of awareness a few hours or days later, the memories of the accident become fuzzy or, in really severe cases … the victim may be completely amnesic. The memories of the accident have become “state-bound”—that is, they are bound to the precise psychophysiological state evoked by the alarm reaction, together with its associated sensory-perceptual impressions. In accessing these psychosomatic state-dependent areas of homeostatic dysfunction, the physician must use techniques that relax the conscious mind and allow access to subconscious content for reframing. The nature of the visit to a physician encourages a patient into more accessible unconscious states, as demonstrated by higher placebo effects when patients present in a hospital setting.121 These labile states of consciousness are quite natural; humans constantly cycle in and out

of different consciousness states.121 These cycles, or ultradian rhythms, are described as alternating cycles of hemispherical dominance that change every 1½ hours. When these cycles are interrupted by behavioral stress, psychosomatic behavioral responses such as ulcers, gastritis, asthma attacks, and rashes develop.175 A change in these rhythms manifests as a period of psychic repose. If an individual is in the midst of performing a task, daydreaming or the perceived need for a rest or coffee break may be the external manifestation of an internally sensed signal of a change in rhythm. This is also a period when one is highly susceptible to hypnotic suggestion. Because these rhythms are very flexible and labile, they can be invoked through hypnosis, or if the physician senses a natural lull indicating a hemispherical switch, a “natural” trance can be induced. Centuries ago in India, practitioners of hatha yoga observed the effect of mental states on the breathing patterns of an individual. With anger, frustration, and mental instability, the breath reflects a short, arrhythmic pattern that mirrors the disturbed psyche of the person. Conversely, when a person is in a peaceful, relaxed, deep meditative state, the breath is long, rhythmic, and barely perceptible. Their discovery formed the basis for the development of breathing exercises called pranayama (literally, regulation or restraint of the vital energy), which aimed to calm the breath so that deep states of meditation and focused concentration could be attained. Current research has affirmed the powerful effect these exercises have on asthma, diabetes, chronic gastrointestinal disorders, and psychosomatic and psychiatric dysfunction.176 Traditional literature on the ethnomedical effects of training the mind and energy (prana, qi, ki, lung) in India, China, and Tibet consistently remark on the antiaging effects of these training methods. Research suggests that meditation may have a deep antiaging response on human functioning, potentially measurable in the epigenetic aging effect.177 Therapeutic exercises that use somatic stimuli to effect changes in the psyche create fertile environments for stimulating the placebo response. A breathing technique used to decrease sympathetic tone or alter nostril predominance for causing shifts in hemispherical activity,178 an exercise to release fascial muscle tension and thereby effect mood-enhancing blood flow in the brain,179,180 and a biofeedback treatment that aids in slowing the heart rate and decreasing negative emotional states169 are all examples of how the psyche can be accessed by the soma. The whole process of eliciting the placebo response involves an attempt to marshal all the reserves and potential for healing through a doctor–patient interaction, engaging both the patient’s mind and body to reestablish homeostatic equilibrium. Therapeutic meditation training has shown benefit in modifying pain.181 Engaging in a formal or traditional method of meditation training may give the patient enhanced insight into the nature of his or her mind and thereby elicit psychological and physical health benefits.182 Trained meditators exhibit unique abilities of mental functioning.183 Medical applications of mind-training methods might be better served by relying on methods with deep cultural experience, at the expense of adopting a liberal, nondenominational, nonsectarian method of “relaxation therapy,” as it appears not all awareness therapies are created equal. Traditional meditation-training methods offer the possibility of sustained and enhanced awareness of mental states, which may contribute to positive medical outcomes.184 Healthcare professionals can use the wisdom of psychosomatic therapies as a central part of their therapeutic protocol. In addition to the specific therapeutic regimen, treatment of the whole patient can be achieved through these harmonious techniques. If physicians could persuade patients to care daily for their emotions, minds, and spirits

CHAPTER 6  the way they care for their hair or teeth, the effectiveness of any prescribed treatment would be greatly enhanced. As a primary therapeutic adjunct and important basis for preventive medicine, this line of treatment is all too often ignored. 

ETHICS There are two forms of “conscious” placebo use by the physician. The use of a placebo as a gentle therapeutic agent by a practitioner is very different from the use of a placebo in a controlled trial in which the possibility of a known therapy is withheld in a treatment group. Some researchers believe that the use of placebos in clinical trials breaches the Declaration of Helsinki, which states that every patient should be assured of the best proven diagnostic and therapeutic method.185 The ethical problems of delivering health care in a research design in which there is a possibility of a favorable outcome, and half of the group is denied access to this possible favorable outcome, make it a troubling issue. The ethical use of placebos has also been questioned in an attempt to determine whether a physician should be deceiving patients during the process of healing.186 Although some writers advocate a restricted use of pure and impure placebos because of their “deceptive” nature,169 it becomes clear in a brief review of the current literature6 that any argument for or against the use of placebo assumes the existence of medical procedures that are free of a potential placebo effect. Brody29 concluded that a placebo can be called the “lie that heals.” However, closer examination shows that it is not the lie that does the healing but, rather, the relationship between the patient and doctor that stimulates a natural self-healing mechanism via psychological, symbolic, and biological intervention29: For some time, medical science has looked almost exclusively at technical means of diagnosis and treatment; the doctor/patient relationship that forms the setting for their application has been naively viewed as a noncontributory background factor, relegated to the amorphous realm of the “art of medicine,” or simply ignored. In this setting, the placebo effect has inevitably been viewed as a nuisance variable, interfering with our ability to elicit “clean data” from clinical trials; and deception in medicine has been seen either as an unimportant side issue or as a tolerated means toward an end. But as the doctor/patient is rediscovered as a worthy focus for medical research and medical education, the placebo effect assumes center stage as one approach to a more sophisticated understanding of this relationship. A physician’s correct understanding of the nature of placebo therapy has been observed as able to coexist with its inaccurate use and

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abuse.41 It has been recommended, however, that (1) a pure placebo should not be prescribed unless the physician has examined the exact indications even more carefully than when prescribing specific therapy, and (2) to avoid missing a disease process that can be easily treated with an empirically proven protocol (e.g., vitamin B12–deficient peripheral neuropathy), the physician should not relax a diagnostic protocol because a patient seems to be responding to a placebo.186 The final ethical hurdle of placebo use, or any medical treatment, for that matter, is the abuse of hope in the patient’s path of healing. It is one thing to make a harmless recommendation that provides no therapeutic value, but it is another to subject a patient to the known consequences of a dangerous procedure in the pursuit of a dubious outcome. Hope can be abused, leading the patient to experience unreasonable suffering.187 

CONCLUSION Health practitioners must be equipped with a better understanding of placebo therapeutics.10,188 For many years now, the study of placebos has been recommended to doctors and other healthcare professionals. The ideal environment for the dissemination of the therapeutic implications of the doctor–patient relationship is in medical schools as a required part of the curriculum. After finding a pattern of misuse and misunderstanding about the nature and efficacy of placebo, Goodwin et al.41 recommended that better education might result in more effective placebo use. In 1938 Houston128 wrote of the need to reaffirm the art of medicine because he perceived a trend in medicine that invested in a concept of the therapeutic doctor–patient interaction as “undisciplined thought.” Houston’s remedy for the intellectual bias that viewed medicine as a “tight, fast-set science” was to emphasize the importance of psychobiology in medical schools129: One of the most hopeful moves in medical education is teaching to first-year students the elements of psychobiology. A system of belief is implanted best in the young. It would be my suggestion that psychobiology be taught in the premedical years, that the doctor/patient relationship be the beginning of medical studies. A deep insight into this fundamental philosophy is a chief concern of the internist.

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7 Positive Mental Attitude John Nowicki, ND, and Michael T. Murray, ND

OUTLINE Introduction, 102 Effect of Attitude, Personality, Emotions on Health, 102 Longevity, 102 Immune Function, 102 Cardiovascular Health, 103

INTRODUCTION A positive mental attitude is one of the foundational elements of good health. This axiom has been contemplated by philosophers and physicians since the time of Plato and Hippocrates. Attitude is reflected by explanatory style, a term developed by noted psychologist Martin Seligman to describe a cognitive personality variable that reflects how people habitually explain the causes of life events.1 Explanatory style was used to describe individual differences in response to negative events during the attributional reformulation of the learned helplessness model of depression developed by Seligman (described in Appendix 12). The Attributional Style Questionnaire developed by Seligman or the Revised OptimismPessimism (PSM) scale of the Minnesota Multiphasic Personality Inventory (MMPI) can be used to determine an individual’s level of optimism. In addition to simple conventional wisdom, modern research has also verified the important role that attitude—the collection of habitual thoughts and emotions—plays in determining the length and quality of life. Specifically, studies using various scales to assess attitude, including the PSM scale of the MMPI, have shown that individuals with a pessimistic explanatory style have poorer health, are prone to depression, are more frequent users of medical and mental health care delivery systems, exhibit more cognitive decline and impaired immune function with aging, and have a shorter survival rate compared with optimists.1–8 One study involved a large cohort of 5566 people who completed a survey at two time points, aged 51 to 56 years at time 1 and aged 63 to 67 years at time 2. This survey included a questionnaire to determine positive psychological well-being by measuring self-acceptance, autonomy, purpose in life, positive relationships with others, environmental mastery, and personal growth. The results showed that people with low positive well-being were 7.16 times more likely to be depressed 10 years later.9 This research highlighted the fact that although life is full of events that are beyond one’s control, people can control their responses to such events. Attitude plays a significant role in determining how people view and respond to the stresses and challenges of life. 

102

Self-Actualization, 103 Clinical Application of Learned Optimism, 104

EFFECT OF ATTITUDE, PERSONALITY, EMOTIONS ON HEALTH Longevity In 1981 the Leisure World Cohort Study undertook a prospective cohort study of nearly 14,000 elderly women and men in a California retirement community to study the relationship between mental attitude and longevity and successful aging.10 Participants completed a postal survey including seven positively worded items from the Zung self-rating depression scale and were followed to death or December 31, 2016 (a 35-year span), whichever came first. In both men and women, a more negative attitude was associated with significantly higher mortality. The risk of death significantly increased by 2% (women) and 4% (men) for each unit decrease in total attitude score. Overall, the multivariable-adjusted hazard ratio (HR) for death for individuals in the lowest versus the highest quarter of total attitude was 1.24 (1.16–1.32) for women and 1.30 (1.19–1.41) for men. Thus strategies to improve mental outlook may help improve the quantity as well as the quality of life. 

Immune Function The importance of attitude to human health has been examined in the links among the brain, emotions, and the immune system. Research in the field of psychoneuroimmunology indicates that every part of the immune system is connected to the brain in some way, either via a direct nervous tissue connection or through the complex language of chemical messengers and hormones. What scientists are discovering is that every thought, emotion, and experience sends a message to the immune system that either enhances or impairs its ability to function. A simplistic view is that positive emotions, such as joy, happiness, and optimism, tend to boost immune system function, whereas negative emotions, such as depression, sadness, and pessimism, tend to suppress it. Studies examining immune function in optimists versus pessimists have demonstrated significantly better immune function in the optimists. Specifically, studies have shown that, compared with pessimists, optimists have increased secretory immunoglobulin-A function, natural killer cell activity, and cell-mediated immunity, which is demonstrated by better ratios of helper to suppressor T-cells.6,11–14

CHAPTER 7  The immune system is so critical to preventing cancer that if emotions and attitude were risk factors for cancer, one would expect to see an increased risk of cancer in people who have long-standing depression or a pessimistic attitude. Research supports this association; for example, smokers who are depressed have a much greater risk of lung cancer than smokers who are not depressed.15 Depression and the harboring of other negative emotions contribute to an increased risk of cancer in several ways. Most research has focused on the effect of depression and other negative emotions on natural killer cells. Considerable scientific evidence has documented the link between a higher risk of cancer and negative emotions, stress, and a low level or low activity of natural killer cells.16 Negative emotions and stress paralyze many aspects of immune function and literally can cause natural killer cells to burst.16,17 Furthermore, the prototypical cancer personality—an individual who suppresses anger, avoids conflicts, and has a tendency to have feelings of helplessness— has lower natural killer cell activity than other personality types.13,14 These studies also indicate that individuals with a personality type that is prone to cancer have an exaggerated response to stress, which compounds the detrimental effects stress has on natural killer cells and the entire immune system. Depression and stress not only affect the immune system but also appear to hinder the cell’s ability to repair damage to DNA. Most carcinogens cause cancer by directly damaging DNA in cells, thereby producing abnormal cells. Some of the most important protective mechanisms against cancer in the cell’s nucleus are the enzymes responsible for the repair or destruction of damaged DNA. Several studies have shown that depression and stress alter these DNA repair mechanisms. For example, in one study, lymphocytes from depressed patients demonstrated impairment in the ability to repair cellular DNA damaged by exposure to x-rays.18,19 Just as research has identified personality, emotional, and attitude traits that are associated with impaired immune function, the field of psychoneuroimmunology has likewise identified a collection of “immune power” traits that include a positive mental attitude; an effective strategy for dealing with stress; and a capacity to confide traumas, challenges, and feelings to oneself and others.16,20 

Cardiovascular Health The cardiovascular system is another system intricately tied to emotions and attitude. The relationship of an optimistic or pessimistic explanatory style with the incidence of coronary heart disease was examined as part of the Veterans Affairs Normative Aging Study, an ongoing cohort study of older men.8 These men were assessed by the MMPI PSM scale. During an average 10-year follow up, 162 cases of incident coronary heart disease occurred: 71 cases of incident nonfatal myocardial infarction, 31 cases of fatal coronary heart disease, and 60 cases of angina pectoris. Men reporting high levels of optimism had a 45% lower risk for angina pectoris, nonfatal myocardial infarction, and coronary heart disease death than men reporting high levels of pessimism. Interestingly, a clear dose–response relationship was found between levels of optimism and each outcome. To illustrate how closely the cardiovascular system is linked to attitude, one study showed how measures of optimism and pessimism affected ambulatory blood pressure.21 Pessimistic adults had higher blood pressure levels than optimistic adults, suggesting that pessimism has broad physiological consequences. Affective well-being (happiness and pleasure) and eudaimonia (sense of autonomy and purposeful engagement with life) have been associated with smaller waist circumference, healthier lipid profiles (e.g., greater high-density lipoprotein cholesterol [HDL-C], lower levels of triglycerides), higher levels of

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Being Needs Self-actualization

Self-esteem Needs Belonging Needs Safety Needs Physiologic Needs Deficit Needs Fig. 7.1  Maslow’s hierarchy of needs.

serum antioxidants, and lower levels of inflammatory markers (e.g., C-reactive protein [CRP], fibrinogen).22 Excessive anger, worrying, and other negative emotions have also been shown to be associated with an increased risk for cardiovascular disease; however, these emotions may simply reflect a pessimistic explanatory style. 

SELF-ACTUALIZATION A physician’s role should include facilitating the health of the patient as well as helping the patient achieve self-actualization, which is a concept developed by Abraham Maslow, the founding father of humanistic psychology. His work and theories were the result of more than 30 years of intense research on psychologically healthy people. Essentially, Maslow was the first psychologist to study healthy people. He strongly believed that the study of healthy people would create a firm foundation for the theories and values of a new psychotherapy. Maslow discovered that healthy individuals are motivated toward self-actualization, a process of “ongoing actualization of potentials, capacities, talents, as fulfillment of a mission (or call, fate, destiny, or vocation), as a fuller knowledge of, and acceptance of, the person’s own intrinsic nature, as an increasing trend toward unity, integration, or synergy within the person.”23 Maslow developed a five-step pyramid of human needs in which personality development progresses from one step to the next. The needs of the lower levels must be satisfied before the next level can be achieved. When needs are met, the individual moves toward well-being and health. Fig. 7.1 displays Maslow’s hierarchy of needs. The primary needs that form the base of the pyramid are basic survival or physiological requirements: the satisfaction of hunger, thirst, sexuality, and shelter. The second step consists of safety needs, which are essential for dealing with the world: security, order, and stability. The individual then progresses to the third step, which involves the ability to love and be loved: belonging. The fourth step involves self-esteem and self-respect: approval, recognition, and acceptance. The final step is self-actualization: the use of one’s creative potential for self-fulfillment. In modern life, a person’s occupation often correlates with the ability to achieve these needs. Table 7.1 provides an application of Maslow’s hierarchy of needs in an occupational environment. Maslow studied self-actualized people and noted that they had strikingly similar characteristics. Some of Maslow’s key findings, in an abbreviated form, include the following: • Self-actualized people perceive reality more effectively than others and are more comfortable with it. They have an unusual ability to

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TABLE 7.1  Practical Application of

Maslow’s Hierarchy of Needs Level of Need

General Rewards

Occupational Factors

Self-actualization

Growth Achievement Advancement Creativity Self-respect Status Prestige

Challenging job Opportunities for creativity Achievement in work Promotion Social recognition Job title High status of job Feedback from the job itself Work groups or teams Supervision Professional associations Health and safety Job security Contract of employment Pay Working conditions

Self-esteem

Belonging

Safety

Physiological

Love Friendship Belongingness Security Stability Protection Food Water Sleep Sex

•

•

•

•

•

•

•

•

•

•

detect the spurious, the fake, and the dishonest in personality. They judge experiences, people, and things correctly and efficiently. They possess an ability to be objective about their own strengths, possibilities, and limitations. This self-awareness enables them to clearly define values, goals, desires, and feelings. They are not frightened by uncertainty. Self-actualized people have an acceptance of self, others, and nature. They can accept their own human shortcomings without condemnation. They do not have an absolute lack of guilt, shame, sadness, anxiety, and defensiveness, but they do not experience these feelings to unnecessary or unrealistic degrees. When they do feel guilty or regretful, they do something about it. Generally, they do not feel bad about discrepancies between what is and what ought to be. Self-actualized people are relatively spontaneous in their behavior and even more spontaneous in their inner lives, thoughts, and impulses. They are unconventional in their impulses, thoughts, and consciousness. They are rarely nonconformists, but they seldom allow convention to keep them from doing anything they consider important or basic. Self-actualized people have a problem-solving orientation toward life instead of a self-orientation. They commonly have a mission in life, some problem outside themselves that enlists much of their energies. In general, this mission is unselfish and is involved with the philosophical and ethical. Self-actualized people have a quality of detachment and a need for privacy. Often, it is possible for them to remain above the battle, to be undisturbed by what upsets others. They are self-governing people who find meaning in being active, responsible, self-disciplined, and decisive rather than being pawns or helplessly ruled by others. Self-actualized people have a wonderful capacity to appreciate the basic pleasures of life, such as nature, children, music, and sex, again and again. They approach these basic experiences with awe, pleasure, wonder, and even ecstasy. Self-actualized people commonly have mystical or “peak” experiences, times of intense emotions in which they transcend the self. During a peak experience, they have feelings of limitless horizons and unlimited power while simultaneously feeling more helpless than ever before. There is a loss of place and time and feelings of

•

•

great ecstasy, wonder, and awe. The peak experience ends with the conviction that something extremely important and valuable has happened, and thus the person is transformed and strengthened by the experience to some extent. Self-actualized people have deep feelings of identification with, sympathy for, and affection for other people despite occasional anger, impatience, or disgust. Self-actualized people have deeper and more profound interpersonal relationships than most other adults, but not necessarily deeper than children’s. They are capable of more closeness, greater love, more perfect identification, and more erasing of ego boundaries than other people would consider possible. One consequence is that self-actualized people have especially deep ties with relatively few individuals, and their circle of friends is small. They tend to be kind or at least patient with almost everyone, yet they speak realistically and harshly of those who they feel deserve it, especially hypocritical, pretentious, pompous, or self-inflated individuals. Self-actualized people are democratic in the deepest possible sense. They are friendly toward everyone, regardless of class, education, political beliefs, race, and color. They believe it is possible to learn something from everyone. They are humble, in the sense of being aware of how little they know in comparison with what could be known and what is known by others. Self-actualized people are strongly ethical and moral. However, their notions of right and wrong and good and evil are often unconventional. For example, a self-actualized person would never consider segregation, apartheid, or racism to be morally right, although it may be legal. Self-actualized people have a keen, unhostile sense of humor. They do not laugh at jokes that hurt other people or are aimed at others’ inferiority. They can make fun of others in general or of themselves when they are foolish or try to be big when they are small. They are inclined toward thoughtful humor that elicits a smile, is intrinsic to the situation, and is spontaneous. Self-actualized people are highly imaginative and creative. The creativeness of a self-actualized individual is not of the special talent type, such as Mozart’s, but rather is like the naive and universal creativeness of unspoiled children. 

CLINICAL APPLICATION OF LEARNED OPTIMISM The new psychology that Maslow’s work referred to may turn out to be “positive clinical psychology.”24 This field of practice was born in 1998 when Martin Seligman chose it as the theme for his term as president of the American Psychological Association.25 Positive clinical psychology aims to change clinical psychology to have an equally weighted focus on both positive and negative functioning.26 The approach is based on five key bodies of empirical findings: (1) the absence of positive well-being leads to the development of disorder over time9; (2) the absence of positive characteristics predicts disorder above and beyond the presence of negative characteristics9; (3) positive characteristics interact with negative life events to predict disorder (so studying only negative life events would produce misleading results)27; (4) many aspects of well-being range from extremely negative functioning, through a neutral midpoint, to positive well-being (possibly including happiness to depression and anxiety to relaxation continuums),28 making it impossible to study exclusively negative or positive well-being; and (5) positive interventions can be as effective as other more commonly used approaches, such as cognitive therapy.29 Positive clinical psychology ultimately involves helping patients become optimistic, which, according to Martin Seligman, is our natural tendency.30 Optimism not only is a necessary step toward achieving optimal health but is also critical to happiness and a higher quality of life.

CHAPTER 7  In many instances, it is not what happens in one’s life that determines one’s direction; to a large degree, it is the response to those challenges that shapes the quality of life and determines one’s level of health. Surprisingly, it is often true that hardship, heartbreak, disappointment, and failure serve as the sparks for joy, ecstasy, compassion, and success. The determining factor is whether these challenges are viewed as stepping-stones or stumbling blocks. A person’s attitude is like his or her physical body: it must be conditioned to be strong and positive. Conditioning an attitude to be positive and optimistic requires adopting specific healthy habits. Four key areas of focus for helping patients develop a positive mental attitude are as follows: 1. Help them become aware of self-talk. Tell them that all people conduct a constant running dialogue in their heads. In time, the things people say to themselves and others percolate down into their subconscious minds. Those inner thoughts, in turn, affect the way people think and feel. Naturally, a steady stream of negative thoughts will have a negative effect on a person’s mood, immune system, and quality of life. The cure is to become aware of self-talk and then to consciously work to feed positive self-talk messages to the subconscious mind. 2. Help them ask better questions. The quality of a person’s life is equal to the quality of the questions habitually asked. For example, if a person experiences a setback, does he or she think, “Why am I so stupid? Why do bad things always happen to me?” or “Okay, what can be learned from this situation so that it never happens again? What can I do to make the situation better?” Clearly, the latter response is healthier. Regardless of the situation, asking better questions is bound to improve one’s attitude. Some examples of questions that can improve attitude and self-esteem when asked regularly include the following: “What am I most happy about in my life right now?” “What am I most excited about in my life right now?” “What am I most grateful about in my life right now?” “What am I enjoying most in my life right now?” “What am I committed to in my life right now?” “Whom do I love? Who loves me?” “What must I do today to achieve my long-term goal?” 3. Help them experience gratitude. A large body of recent work has suggested that people who are more grateful have higher levels of well-being and are happier, less depressed, less stressed, and more satisfied with their lives and social relationships.31,32 Gratitude appears to have one of the strongest links with mental health of any character trait. Helping instill a sense of gratitude has been shown to be a very successful intervention. In one study, participants were randomly assigned to one of six therapeutic interventions designed to improve the participants’ overall quality of life.33 Of these six interventions, it was found that the biggest short-term effects came from a “gratitude visit,” where participants wrote and delivered a letter of gratitude to someone in their lives. This simple gesture showed a rise in happiness scores by 10% and a significant fall in depression scores, the results of which lasted up to 1 month after the visit. The act of writing “gratitude journals,” in which participants wrote down three things they were grateful for every day, had longer-lasting effects on happiness scores. The greatest benefits

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with this practice were usually found to occur around 6 months after it began. Similar practices have shown comparable benefits. 4. Help them set positive goals. Learning to set achievable goals is a powerful method for building a positive attitude and raising self-esteem. Achieving goals creates a success cycle: a person feels better about him- or herself, and the better he or she feels, the more likely he or she is to succeed. Some guidelines for helping patients set healthy goals include the following: • Be specific. The more clearly the goal is defined, the more likely it will be achieved. For example, if a person wants to lose weight, he or she should define the desired weight and the body fat percentage or measurements to be achieved. • State the goal in positive terms and in the present tense; avoid negative words. It’s better to say, “I enjoy eating healthy, low-calorie, nutritious foods” than to say, “I will not eat sugar, candy, ice cream, and other fattening foods.” • Make the goal attainable and realistic. Start out with goals that are easily attainable, like drinking six glasses of water a day or switching from white to whole-grain bread. Initially choosing easily attainable goals creates a success cycle that helps build a positive self-image. Little things add up to make a major difference in the way a person feels about him- or herself. Counseling is necessary for the severely pessimistic individual. Forms of cognitive therapy appear to be the most useful therapy. Cognitions comprise the whole system of thoughts, beliefs, mental images, and feelings. Cognitive therapy can be as effective as the use of antidepressant drugs in the treatment of moderate depression; in addition, there tends to be a lower risk of relapse—the return of depression—with cognitive therapy.34 One reason for this is that cognitive therapy teaches people practical skills they can use to combat depression anytime, anywhere, and every day for the rest of their lives. Cognitive therapy avoids the long, drawn-out (and expensive) process of psychoanalysis. It is a practical, solution-oriented psychotherapy that teaches skills a person can apply to improve quality of life. Mental health specialists trained in cognitive therapy seek to change the way the depressed person consciously thinks about failure, defeat, loss, and helplessness. To do so, they employ five basic tactics that help patients do the following: • Recognize the automatic negative thoughts that flit through consciousness at the times when they feel the worst. • Dispute the negative thoughts by focusing on contrary evidence. • Learn a different explanation to dispute the automatic negative thoughts. • Avoid rumination (the constant churning of a thought in one’s mind) by helping the patient better control his or her thoughts. • Question depression-causing negative thoughts and beliefs and replace them with empowering, positive thoughts and beliefs.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Peterson C, Seligman M, Valliant G. Pessimistic explanatory style as a risk factor for physical illness: a thirty-five year longitudinal study. J Pers Soc Psychol. 1988;55:23–27. 2. Maruta T, Colligan RC, Malinchoc M, Offord KP. Optimism-pessimism assessed in the 1960s and self-reported health status 30 years later. Mayo Clin Proc. 2002;77:748–753. 3. Taylor SE, Kemeny ME, Reed GM, et al. Psychological resources, positive illusions, and health. Am Psychol. 2000;55:99–109. 4. Schweizer K, Beck-Seyffer A, Schneider R. Cognitive bias of optimism and its influence on psychological well-being. Psychol Rep. 1999;84: 627–636. 5. Chang EC, Sanna LJ. Optimism, pessimism, and positive and negative affectivity in middle-aged adults: a test of a cognitive-affective model of psychological adjustment. Psychol Aging. 2001;16:524–531. 6. Segerstrom SC. Optimism, goal conflict, and stressor-related immune change. J Behav Med. 2001;24:441–467. 7. Maruta T, Colligan RC, Malinchoc M, Offord KP. Optimists vs pessimists: survival rate among medical patients over a 30-year period. Mayo Clin Proc. 2000;75:140–143. 8. Kubzansky LD, Sparrow D, Vokonas P, Kawachi I. Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative aging study. Psychosom Med. 2001;63:910–916. 9. Wood AM, Joseph S. The absence of positive psychological (eudemonic) well-being as a risk factor for depression: a ten year cohort study. J Affect Disord. 2010;122:213–217. 10. Paganini-Hill A, Kawas CH, Corrada MM. Positive mental attitude associated with lower 35-year mortality: the leisure world cohort study. J Aging Research. 2018;2126368. PubMed PMID: 30595919. 11. Brennan FX, Charnetski CJ. Explanatory style and immunoglobulin A (IgA). Integr Physiol Behav Sci. 2000;35:251–255. 12. Kamen-Siegel L, Rodin J, Seligman ME, Dwyer J. Explanatory style and cell-mediated immunity in elderly men and women. Health Psychol. 1991;10:229–235. 13. Imai K, Nakachi K. Personality types, lifestyle, and sensitivity to mental stress in association with NK activity. Int J Hyg Environ Health. 2001;204:67–73. 14. Segerstrom SC. Personality and the immune system: models, methods, and mechanisms. Ann Behav Med. 2000;22:180–190. 15. Jung W, Irwin M. Reduction of natural killer cytotoxic activity in major depression: interaction between depression and cigarette smoking. Psychosom Med. 1999;61:263–270. 16. Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev Psychol. 2002;53:83–107.

17. Maddock C, Pariante CM. How does stress affect you? An overview of stress, immunity, depression and disease. Epidemiol Psychiatr Soc. 2001;10:153–162. 18. Kiecolt-Glaser JK, Stephens R, Lipitz P, et al. Distress and DNA repair in human lymphocytes. J Behav Med. 1985;8:311–320. 19. Glaser R, Thorn BE, Tarr KL, et al. Effects of stress on methyltransferase synthesis: an important DNA repair enzyme. Health Psychol. 1985;4:403–412. 20. Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology and cancer: fact or fiction? Eur J Cancer. 1999;35:1603–1607. 21. Raikkonen K, Matthews KA, Flory JD, et al. Effects of optimism, pessimism, and trait anxiety on ambulatory blood pressure and mood during everyday life. J Pers Soc Psychol. 1999;76:104–113. 22. Steptoe A, Demakakos P, de Oliveira C, Wardle J. Distinctive biological correlates of positive psychological well-being in older men and women. Psychosomatic Medicine. 2012;74(5):501–508. PubMed PMID: 22511728. 23. Maslow A. The Farther Reaches of Human Nature. New York: Viking; 1971. 24. Lambert MJ, Erekson DM. Positive psychology and humanistic tradition. J Psychother Integration. 2008;18:222–232. 25. Seligman MEP, Csikszentmihalyi M. Positive psychology: an introduction. Am Psychol. 2000;55:5–14. 26. Wood AM, Tarrier N. Positive clinical psychology: a new vision and strategy for integrated research and practice. Clin Psychol Rev. 2010;30(7):819–829. 27. Johnson J, Gooding PA, Wood AM, et al. Resilience to suicidal ideation in psychosis: positive self-appraisals buffer the impact of hopelessness. Behav Res Ther. 2010;48(9):883–889. 28. Wood AM, Taylor PT, Joseph S. Does the CES-D measure a continuum from depression to happiness? Comparing substantive and artifactual models. Psychiatry Res. 2010;177:120–123. 29. Geraghty AWA, Wood AM, Hyland ME. Attrition from self-directed interventions: Investigating the relationship between psychological predictors, intervention content and dropout from a body dissatisfaction intervention. Social Sci Med. 2009;71:31–37. 30. Seligman M. Learned Optimism. New York: Knopf; 1991. 31. Wood AM, Froh JJ, Geraghty AW. Gratitude and well-being: a review and theoretical integration. Clin Psychol Rev. 2010;30(7):890–905. 32. Wood AM, Joseph S, Maltby J. Gratitude predicts psychological well-being above the Big Five facets. Pers Individ Dif. 2009;46:443–447. 33. Seligman MEP, Steen TA, Park N, Peterson C. Positive psychology progress: empirical validation of interventions. Am Psychol. 2005;60:410–421. 34. Casacalenda N, Perry JC, Looper K. Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry. 2002;159:1354–1360.

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Primary and Adjunctive Diagnostic Procedures During the 20th century, tremendous progress was made in the development of laboratory procedures for the diagnosis of disease. However, this work focused primarily on pathological processes—typically advanced disease; little was done to help the physician recognize physiological abnormalities before they progress to the pathological stage. The problem is further aggravated for doctors of preventive/integrative/functional/natural medicine, who need to evaluate in an objective manner the nutritional status, lifestyle, physiological competency, toxic load, and vitality of their patients. The few available tests that exist tend to be oriented to measuring absolute values rather than functional indices and generally indicate abnormal values only after serious dysfunction develops. In this section, we have compiled useful assessment methodologies we believe will greatly aid healthcare professionals who want more objective tests in their evaluation of the pathophysiological status of their patients and the causes of dysfunction. These are not meant to replace the standard, pathologically oriented, diagnostic procedures. Rather, we are encouraging the use of methodologies that aid in the early diagnosis of disease susceptibility, quantification of the processes that usually precede clinical disease, and ways to objectively assess foundational causes like functional nutritional deficiencies and toxic load. Where possible, preference is given to tests that measure the uniqueness of the patient’s biochemistry rather than abstract absolute values. In keeping with the metabolic and scientific orientation of this textbook, the emphasis has been placed on those procedures that have strong support in the research literature. Most of these laboratory procedures are on the cutting edge of our understanding of the assessment of the physiological function of metabolically unique individuals. Because it is an emerging field, few experts exist, and many are employed by or associated with the commercial laboratories performing the procedures.

     

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8 Apoptosis in Health and Diseases Lise Alschuler, ND, and Aristo Vojdani*, PhD, MSc, CLS

OUTLINE Introduction, 107 Measurable Features of Apoptosis for Research Purposes, 107 Different Stages of Apoptosis, 108 Apoptosis Is Induced by Chemicals to Control Malignancy, 109 Clinical Applications, 110 Apoptosis in Cancer, 110

Apoptosis in Autoimmune Diseases, 110 Apoptosis During Viral Infection, 111 Apoptosis in Acquired Immunodeficiency Syndrome, 111 Apoptosis in the Heart and Brain, 111 Conclusions, 111

INTRODUCTION

essentially the interpretation of an apoptotic assay is fraught with unknowns—the significance of any result being dependent on a lack of a reference standard, itself determinant upon the type and number of cells assayed, the duration of apoptosis, and the timing and duration of the test.9

Apoptosis is a distinct form of cell death controlled by an internally encoded suicide program. It is believed to occur in the majority of animal cells. It is a distinct event that triggers characteristic morphological and biological changes in the cellular life cycle. It is common during embryogenesis, normal tissue and organ involution, and cytotoxic immunological reactions, and it occurs naturally at the end of the life span of differentiated cells. Apoptosis can also be induced in cells by the application of a number of different agents, including physiological activators, heat shock, bacterial toxins, oncogenes, chemotherapeutic drugs, various toxic chemicals, ultraviolet and γ-radiation, and hypoxia. When apoptosis occurs, the nucleus and cytoplasm of the cell often fragment into membrane-bound apoptotic bodies, which are then phagocytized by neighboring cells. Alternatively, during necrosis, cell death occurs by direct injury to cells, resulting in cellular lysing and the release of cytoplasmic components into the surrounding environment, often inducing an inflammatory response in the tissue. Apoptosis may occur in one cell, leaving surrounding cells unaffected, as opposed to necrosis, which affects multiple cells simultaneously. A landmark of cellular self-destruction by apoptosis is the activation of nucleases and proteases that degrade the higher-order chromatin structure of the DNA into fragments of 50 to 300 kilobases and subsequently into smaller DNA pieces of about 200 base pairs in length. Activation of proteases, notably aspartate-specific cysteinyl proteases, referred to as caspases, is of primary relevance to apoptosis. Caspase-3 is considered to be the key mediator of apoptosis of mammalian cells, with apoptotic cells characterized by significant caspase 3 activation.1 Caspase-3 expression may be measured with immunohistochemical staining with caspase 3 antibodies at 1:50 dilution (DAKO, Carpinteria, CA).2 Using fluorescent-labeled reagents, it is also possible to tag the DNA break and identify the percentage of apoptotic cells with a high degree of accuracy.3–8 Unfortunately, there is no test for apoptosis that is clinically relevant. Although there are methodological limitations,

Measurable Features of Apoptosis for Research Purposes One of the most easily measured features of apoptotic cells is the breakup of the genomic DNA by cellular nucleases. These DNA fragments can be extracted from apoptotic cells and result in the appearance of DNA laddering when the DNA is analyzed by agarose gel electrophoresis. The DNA of nonapoptotic cells, which remains largely intact, does not display this laddering on agarose gels during electrophoresis. The large number of DNA fragments appearing in apoptotic cells results in a multitude of 3′-hydroxyl termini of DNA ends. This property can also be used to identify apoptotic cells by labeling the DNA breaks with fluorescent-tagged deoxyuridine triphosphate nucleotides. The enzyme terminal deoxynucleotidyl transferase catalyzes a template-independent addition of deoxyribonucleotide triphosphates to the 3′-hydroxyl ends of double- or singlestranded DNA. A substantial number of these sites are available in apoptotic cells, providing the basis for the single-step fluorescent labeling and flow cytometric method. Nonapoptotic cells do not incorporate significant amounts of the fluorescent-tagged deoxyuridine triphosphate nucleotides due to the lack of exposed 3′-hydroxyl DNA ends. Apoptosis can also be characterized by changes in cell membrane structure. During apoptosis, the cell membrane’s phospholipid asymmetry changes—phosphatidylserine is exposed on the outer membrane, whereas membrane integrity is maintained. Annexin V specifically binds phosphatidylserine, whereas propidium iodide is a DNA-binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells stain positive for annexin V and negative for propidium iodide; necrotic cells stain positive for both, and live cells stain negative for both.5

*Previous edition contributor

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Primary and Adjunctive Diagnostic Procedures INDUCER STAGE • Toxic chemicals • Radiation • Cytokines • Withdrawal of survival factors (GH)

Chemicals Toxins Ultraviolet Cancer drugs

Live cell

Early apoptotic cell

Detection of % apoptosis by staining of membrane annexin or DNA single-strand break Late apoptotic cell Fig. 8.1 Detection of apoptosis using damaged membrane or DNA ­single-strand break and flow cytometry.

• Oxidants • Chemotherapy agents • Hormones

SENSORS/TRIGGERS or TRANSDUCING DEATH SIGNALS • Reactive oxygen • P53, C-myc

• Superoxide dismutase mutation • Fas signaling

THE EXECUTIONER • IL1-β converting enzyme • Granzymes

• Serine protease • Cysteine protease • Cyclin-dependent kinases CELL DEATH

Fig. 8.3  Various stages of “inside-out” cell death or apoptosis.

Fig. 8.2  Separation of cells by flow cytometry and detection of apoptotic population.

This process of apoptosis and its analysis by flow cytometry are shown in Figs. 8.1 and 8.2. Another assessment of apoptosis involves ex vivo cell analysis. Specifically, the expression of active caspase-3 along with the Bcl-2:Bax ratio as markers of apoptosis can be measured. Immunohistochemical staining will reveal the expression of these apoptotic-related proteins, caspase-3 and cleaved caspase-3; the latter is indicative of apoptosis.10 Bcl-2 is antiapoptotic gene product that exists in ratio to Bax and Bak, which are proapoptotic gene products. This ratio is indicative of the degree of apoptosis, with a decreased Bcl-2:Bax ratio indicative of apoptosis. Cells from Bax(−/−) and Bak(−/−) knockout animals do not respond to apoptosis inducers. In these cells, cytochrome C is not released from the mitochondrial membrane to initiate the caspase cascade.11 Thus Bax and Bak are critical to apoptosis, and their expression in relation to Bcl-2 is highly correlative to apoptosis. 

Different Stages of Apoptosis The process of apoptosis is divided into three stages: • Induction • Sensing or triggering • Execution

These stages of apoptosis are depicted in Fig. 8.3. Induction represents the initial events that signal a cell so that apoptosis may begin. This induction phase may be induced by various physical agents, such as toxic chemicals, hypoxia, radiation, chemotherapy agents, hormones, and CD95 or Fas ligation. It has been proposed that the induction stage of apoptosis is prevented by many antioxidants (vitamin C, β-carotene, and vitamin E) and also by various biological response modifiers, including lentinan, thymic hormones, viral antigens, and cytokines. It is important to note that both extrinsic and intrinsic pathways of apoptosis induction converge in the mitochondria and that the prevention or initiation of apoptosis from this point is the result of cellular redox status.12 Persistent low to moderate oxidation is consistent with the prevention of apoptosis. Low to moderate oxidative stress within the mitochondrial membrane activates Bcl-2. Bcl-2 maintains the intracellular redox status at a level that is optimal for the cell. Bcl-2 does this by increasing the mitochondrial burn rate of oxygen, thereby increasing electron leakage and oxygen concentration, relative to hydrogen peroxide, in the mitochondrial membrane. This reduces the permeability of the inner mitochondrial membrane and the opening of apoptotic pores. Further, Bcl-2 physically sequesters proapoptotic proteins, Bax and Bak.13 Bax and Bak normally facilitate the release of cytochrome C from the inner mitochondrial membrane and out into the cytosol, where it initiates the caspase cascade. However, when oxidative stress is acute or high, the inhibitory role of Bcl-2 is altered, and apoptosis can occur. Also, higher levels of reactive oxidative stress generate more hydrogen peroxide within the mitochondria, which, in turn, oxidizes other mitochondrial components, such as cardiolipin, and inner membrane phospholipid. Oxidized cardiolipin moves to the outer mitochondrial membrane and recruits Bax and Bak, thus enabling the release of cytochrome C through Bax- and Bak-controlled pores, finally activating caspases and apoptosis.14 Also in response to higher oxidative stress, p53 translocates from the cell’s nucleus to the mitochondria, where it is de-ubiquitinated and subsequently activates Bax- and Bak-induced apoptosis.15

CHAPTER 8  There is, however, a limit to the proapoptotic response to oxidative stress. When oxidative stress is overwhelmingly high and/or prolonged, oxidative damage occurs to cytochrome C and to downstream caspases preventing apoptosis. There are other apoptotic escape mechanisms present in cells as well. Mitochondrial paraoxonase enzymes PON2 and PON3 interact with ubiquinone to reduce oxygen release. This mitigates oxidation of cardiolipin, creating a resistance to apoptosis. In fact, PON2 and PON3 have been established as key factors in the prevention of atherosclerosis because endothelial and macrophage death are the basis of atherogenic plaques.16 The induction of apoptosis is entirely dependent on the redox state of the cell and the mitochondrial response to oxidation. Mitochondria can respond to moderate or acute oxidative stress by initiating apoptosis; however, excessive and/or prolonged oxidative stress prevents apoptosis. Glutathione plays a major role in controlling mitochondrial oxidative stress. Reduced glutathione (GSH) donates electrons to reactive oxygen species (ROS), thereby preventing the generation of hydrogen peroxide. In the course of donating the electron, glutathione itself becomes oxidized (GSSG). Oxidized glutathione is then regenerated back to its reduced state through the action of glutathione reductase. On the one hand, the presence of GSH facilitates the destruction of hydrogen peroxide, thereby preventing the release of cytochrome C and delaying apoptosis. This allows the cell to undergo repair, instead of apoptosis, when the oxidative stress is temporary and/or low. On the other hand, by regulating the amount of oxidation, GSH preserves mitochondrial membrane integrity and cytochrome C, ensuring that the capacity for apoptosis in the face of high and/or prolonged oxidative stress is present. If there is a deficiency of reduced glutathione or damage to glutathione reductase (for instance by arsenic trioxide or lead) in the context of high oxidative stress, the cell will be unable to initiate apoptosis.17 Instead, the cell will be forced to undergo unprogrammed cell death, or necrosis. This is an inflammatory event and will ultimately further contribute to the regional oxidative stress. Thus the induction of apoptosis is intimately connected with the cellular redox potential of cells, itself regulated primarily by glutathione. The induction stage is followed by a decision on whether or not the cell will undergo apoptosis. The decision to die is under the control of a number of different pathways or cellular sensors that induce the apoptosis signal, which then triggers the central mechanisms. During this stage, enzymes such as interleukin-1β–converting enzymes, serine protease, cysteine protease, granzymes, and cyclin-dependent kinases become activated. Once activated, these enzymes dismantle the cell and trigger the cell-surface changes that cause direct cell recognition and engulfment of the dying cells by phagocytes. These central events are prevented by various antioxidants and biological response modifiers. 

Apoptosis Is Induced by Chemicals to Control Malignancy Many chemicals have the capacity to bind to DNA, form DNA adducts, or cause DNA single-strand breaks, possibly leading to cancer. However, the body is equipped with many factors, enzymes, suppressor genes, and cellular sensors, all with the capacity to prevent the consequences of this DNA damage by activating apoptosis-inducing signals. The role of apoptosis in regulating tissue growth is readily apparent in the simple equation in which the rate of growth is equal to the difference between the rates of cell proliferation and cell death. Thus tissues expand if the rate of proliferation exceeds the rate of cell death. This is one of the reasons for suggesting that defects in apoptosis may contribute to the transformed state.

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An important prediction of the relevance of apoptosis to malignancy is that the rate of apoptosis versus mitosis should influence the behavior of a tumor. Recently, the relationship between the apoptotic and mitotic indexes in a tumor was demonstrated as predictive of outcome: a higher ratio of apoptosis to mitosis within the tumor correlated with a positive prognosis. Further, it was found that this was not simply a function of cell death per se. Tumors with a high incidence of necrosis rather than apoptosis were correlated with a poor prognosis. It therefore follows that treatments or conditions that favor apoptosis should have desirable effects and that defects in the pathways leading to apoptosis are likely to play important roles in the process of oncogenesis.6,7 Many reactive chemicals and drugs, such as acetaminophen, diquat, carbon tetrachloride, quinones, cyanide, polyhydroxy polyether, methyl mercury, and organotin, have been implicated in apoptosis (programmed cell death) and necrosis (toxic cell death).18–25 Most research on chemical induction of apoptosis is carried out with primary cultures of cell lines (e.g., neurons, thymocytes, carcinoma cells, leukemia cells, neuroblastoma, breast cancer cells, lymphoma); little has been published on the in vivo effects of chemicals on apoptotic cells in animal models and none in humans. Therefore it was of interest to examine the effects of exposure to low levels of benzene, as well as through drinking water concentrations of up to 14 ppb, on the apoptotic cell population, as well as to examine possible changes in the cell cycle progression.18 Evidence is sufficient for the carcinogenicity of benzene in humans; therefore there is no safe level of exposure to this chemical or its metabolites. Published case reports, a case series, epidemiological studies, and both cohort and case-control studies have shown statistically significant associations between leukemia and occupational exposure to benzene and benzene-containing solvents.26,27 It has been indicated that possibly 800,000 persons are exposed to benzene from coke-oven emissions at levels of less than 0.1 ppm, and 5 million may be exposed to benzene from petroleum refinery emissions at levels of 0.1 to 1 ppm. Since these studies, numerous chemicals have been implicated in apoptosis (or programmed cell death), which arises from damage to DNA. One of the authors, Vojdani, along with collaborators, hypothesized that in individuals with a certain genetic makeup, benzene or its metabolites act as haptens, which may induce programmed cell death. The study involved a group of 60 male and female subjects who were exposed to benzene-contaminated water (at concentrations up to 14 ppm for a period of 3–5 years).18 For comparison, a control group consisting of 30 healthy males and females with a similar age distribution and without a history of exposure to benzene were recruited. Using flow cytometry, the peripheral blood lymphocytes of both groups were tested for the percentage of apoptotic cell population. When exposed individuals were compared with the control group, statistically significant differences between each mean group were detected (27.5 ± 2.4 and 10 ± 2.6, respectively), indicating an increased rate of apoptosis in 86.6% of exposed individuals (P < 0.0001; Mann–Whitney U-test). Flow cytometry analysis of apoptosis in a healthy control and a patient with chronic fatigue syndrome is shown in Fig. 8.4. It has been demonstrated that benzene induction of apoptosis is caused by a discrete block of the cell-cycle progression. There is a tendency for normal cells to commit “suicide” when deprived of usual growth factors or physical contact with their neighbors due to chemical exposure, which may represent a built-in defense against metastasis. Prompt activation of apoptosis in tumor cells that leave their native tissue presumably eliminates many metastatic cells before they have a chance to proliferate. In cancer, it is tumor cells that neglect to sacrifice themselves or forget to die. Researchers increasingly describe cancer as

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0 200 400 600 800 1000 0 200 400 600 800 1000 Fig. 8.4  Enhanced apoptotic cell population in benzene-exposed individuals with chronic fatigue syndrome. Flow cytometry analysis of apoptotic cell population in negative control cells (HL-60 leukemic cell line), positive control cells (HL-60 leukemic cells treated with the Apogen camptothecin), control subjects, and benzene-exposed individuals. Peripheral blood leukocytes were isolated, cultured for 12 hours, fixed in paraformaldehyde, labeled with fluorescent-tagged deoxyuridine triphosphate nucleotides, and analyzed for apoptosis by flow cytometry.

a disease involving both excessive proliferation of cells and abandonment of their ability to die. The dysregulation of apoptosis in malignant cells underlies both the initiation and progression of cancer. Cancer develops after a cell accumulates mutations in several genes that control cell growth and survival. When a mutation seems irreparable, the affected cell usually kills itself rather than risk becoming deranged and potentially dangerous. However, if the cell does not die, it or its progeny may live long enough to accumulate mutations that enable it to divide uncontrollably and metastasize. In many tumors, genetic damage apparently fails to induce apoptosis because the constituent cells have inactivated the gene that codes for the p53 protein. This protein can lead to activation of the cell’s apoptotic machinery when DNA is injured by environmental agents, such as benzene or its metabolites. Therefore it is important to study cell suicide in health and diseases. 

CLINICAL APPLICATIONS Apoptosis in Cancer The failure of apoptosis in malignant cells in the context of irreparable DNA damage leads to tumor progression. Cancer therapies, namely chemotherapy and radiation, control cancer by inflicting cell damage, which, in turn, triggers apoptosis. Unfortunately, >50% of all human cancers involve a mutation of p53, a central gene in apoptosis. p53 stimulates both the extrinsic death receptor pathway of apoptosis as well as the intrinsic mitochondrial pathway involving a decreased Bcl2:Bax ratio. Thus it is imperative to find therapies that promote apoptosis independent of p53. Promising therapies in this regard include curcumin28 derived from Curcuma longa, genistein derived from soy,29

and resveratrol,30 all of which are under investigative study for this application. Another promising cancer treatment involves the use of recombinant human apoptosis ligands to induce tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). These ligands induce apoptosis via TRAIL, a selective death receptor pathway in a broad range of cancer cell lines, while sparing most normal cell types.31 The therapeutic potential for TRAIL-inducing ligands is most promising in combination with cytotoxic chemotherapy agents. Advances in cancer therapy are likely to come in the area of targeted therapies, the majority of which trigger specific receptor-driven pathways that culminate in apoptosis. The centrality of apoptosis induction in cancer cannot be overstated. 

Apoptosis in Autoimmune Diseases In cancer, it is the tumor cells that forget to die; in autoimmunity, immune cells fail to die when they are supposed to. Virtually all tissues harbor apoptotic cells at one time or another. Damaged cells usually commit suicide for the greater good of the body; when this does not occur, disease may develop. Autoimmunity occurs when the antigen receptors on immune cells recognize specific antigens on healthy cells and cause the cells bearing those particular substances to die. Autoimmune disease results from perpetuated immune-mediated tissue destruction and can involve immune cells that are resistant to apoptosis. Under normal conditions, the body allows a certain number of self-reactive lymphocytes to circulate. These cells normally do little harm, but they can become overactive through several processes. For instance, if these reactive lymphocytes recognize some foreign antigen such as microbes on food and haptenic chemicals, then exposure to that antigen causes them to become excited. If, due to molecular

CHAPTER 8  mimicry, these antigens are similar to normal tissues, the activated cells may expand their numbers and attack the healthy tissue, thus causing an autoimmune disease.3,32,33 Autoimmune reactions usually are self-limited—they disappear when the antigens that originally set them off are cleared away. In some instances, however, the autoreactive lymphocytes survive longer than they should and continue to induce apoptosis in normal cells. Some evidence in animals and humans has indicated that extended survival of autoreactive cells is implicated in at least two chronic autoimmune syndromes—systemic lupus erythematosus and rheumatoid arthritis. In other words, the lymphocytes undergo too little apoptosis, with the result that normal cells undergo too much.34,35 

Apoptosis During Viral Infection Disturbance in the regulation of apoptosis is a component in various diseases. Viral illnesses are among the diseases caused by apoptosis dysregulation. After entering a cell, viruses attempt to shut down the cell’s ability to make any proteins except those needed to produce more virus. This act of stalling host protein synthesis is enough to induce many kinds of cells to undergo apoptosis. If the host cell dies, the virus is also eliminated. Therefore certain viruses have evolved ways to inhibit apoptosis in the cells they infect. Epstein–Barr virus, which causes mononucleosis and has been linked to lymphomas in humans, uses a mechanism that has been seen in other viruses. Epstein–Barr virus produces substances that inhibit apoptosis. Papillomavirus, a major cause of cervical cancer, inactivates p53, a central mediator of apoptosis. Cowpox virus, a relative of which is used as the smallpox vaccine, is another virus that inhibits caspase activation and attendant apoptosis. Investigators interested in antiviral therapy are now exploring ways to block the activity of the antiapoptotic molecules manufactured by viruses.34 

Apoptosis in Acquired Immunodeficiency Syndrome Induction of apoptosis by viruses in healthy cells is believed to contribute to the immune deficiency found in patients with acquired immunodeficiency syndrome (AIDS). In these patients, infection with human immunodeficiency virus (HIV) causes T-helper cells to die. As T-helper cells gradually disappear, cytotoxic cells, such as natural killer cells, also perish through apoptosis because they cannot survive without the growth signals produced by T-helper cells. When the number of T cells dwindles, so does the body’s ability to fight infections, especially viral and parasitical infections. Researchers have shown that many more helper cells succumb in addition to those that are infected with HIV. It is also highly probable that a large number of the cells die through apoptosis. Apparently, Fas plays a crucial role in this process. Normally, T cells make functional Fas only after they have been active for a few days and are ready to die. However, helper cells from AIDS patients may display high amounts of functional Fas even before the cells have encountered an antigen. This display of Fas would be expected to cause the cells to undergo apoptosis prematurely whenever they encounter Fas ligand on other cells (such as on T cells already activated against HIV or other microbes). In addition, if the primed cells encounter the antigen recognized by their receptors, they may trigger their own death. It is also possible that oxygen free radicals trigger the suicide of virus-free T cells. These highly reactive substances are produced by inflammatory cells drawn to infected lymph nodes in patients with HIV. Free radicals can damage DNA and membranes in cells. They will cause necrosis if they do extensive damage, but they can induce apoptosis if the damage is more subtle. In support of the free-radical theory, researchers have found that molecules capable of neutralizing free radicals prevent apoptosis in T cells obtained from patients with AIDS.34,35

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Therapies with antiapoptotic medication, such as Trolox, a water-soluble analog of vitamin E that prevents oxidative stress, and pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor-κB, are now the focus of AIDS and autoimmune disease studies.36,37 Additionally, protease inhibitors, which are the mainstay of HIV therapy, inhibit apoptosis in immune cells.38 The mechanism underlying the apoptosis inhibition is as of yet unknown, but interestingly, supratherapeutic doses of protease inhibitors have an opposite, proapoptotic effect. 

Apoptosis in the Heart and Brain In contrast to cancer, where cells forget to die and insufficient apoptosis occurs, excessive apoptosis accounts for much of the cell death that follows heart attacks and strokes. In the heart, vessel blockage decimates cells that were fully dependent on the vessel. Those cells die by necrosis, partly because they are catastrophically starved of the oxygen and glucose they need to maintain themselves and partly because calcium ions, which are normally pumped out of the cell, rise to toxic levels. Over the course of a few days, cells surrounding the dead zone, which initially survive because they continue to receive nourishment from other blood vessels, can die as well. Later, however, many cells die by necrosis after being overwhelmed by the destructive free radicals that are released when inflammatory cells swarm into the dead zone to remove necrotic tissue. The less injured cells commit suicide by apoptosis. If the patient is treated by restoring blood flow, still more cells may die by necrosis or apoptosis because reperfusion leads to a transient increase in the production of free radicals. Similarly, in strokes due to inflammation, the release of such neurotransmitters as glutamate leads to necrosis and apoptosis. Understanding of the factors that lead to the tissue death accompanying heart attack, stroke, and reperfusion has led to new ideas for treatment. Notably, cell death might be limited by drugs and other agents that block free-radical production or inhibit proteases. Apoptosis also accounts for much of the pathology seen in such diseases as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (Lou Gehrig’s disease), which are marked by the loss of brain neurons. Elevated apoptosis in these neurological diseases seems to be related to a lack of production of the nerve growth factor and to free-radical damage. It seems likely that a combination of such factors could cause many cells to destroy themselves. Manipulation of this process of cell killing may help in treating these neurological diseases. Studies in animal models imply that long-term delivery of nerve growth factors could protect against programmed cell death in these conditions. Therefore a greater understanding of the mechanisms involved in cell death should greatly enhance those important steps.32,36,39 

CONCLUSIONS Apoptosis and cell proliferation play an important role in development, differentiation, homeostasis, and aging.4–8 The balance established between these two processes depends on various growth and death signals that are influenced by diet, nutrition, lifestyle, and other environmental factors. When the equilibrium between life and death is disrupted by aberrant signals (e.g., low levels of antioxidants in the blood or tissue cells), either tissue growth or atrophy occurs. Under normal conditions with optimal nutritional factors, tissue homeostasis is sustained by balancing the effects of mitosis and apoptosis. The importance of this balance can clearly be seen when one of these processes becomes predominant (Fig. 8.5). The apoptotic potential within each cell is critical for the health of the host. Apoptosis is

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Primary and Adjunctive Diagnostic Procedures an elegant response to oxidative stress. This seemingly heroic sacrifice of self for the greater good underpins healthy living. Imbalance of apoptosis regulators, genetic mutations, and viral infections thwarts the healing effect of apoptosis. Finding ways to restore apoptotic and redox balance is critical to health.

REFERENCES See www.expertconsult.com for a complete list of references.

Fig. 8.5  The balance or imbalance between the rate of apoptosis and mitosis determines tissue homeostasis, atrophy, cell proliferation, and the development of cancer.

REFERENCES 1. Yang Min, Antoine Daniel J, Weemhoff James L, et al. Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia-reperfusion injury in mice. Liver Transpl. 2014;20(11):1372–1382. 2. Mohamed AK, Magdy M. Caspase 3 role and immunohistochemical expression in assessment of apoptosis as a feature of H1N1 vaccinecaused drug-induced liver injury (DILI). Electron Physician. 2017;9(5):4261–4273. 3. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. 4. White E. Life, death and the pursuit of apoptosis. Genes Dev. 1996;10:1–15. 5. Jarvis WD, Kolesnick RN, Fornari FA, et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A. 1994;91:73–77. 6. Green DR, Martin SJ. The killer and the executioner: how apoptosis controls malignancy. Curr Opin Immunol. 1995;7:694–703. 7. Arends MJ, McGregor AH, Wyllie AH. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras and HPV oncogenes. J Pathol. 1994;144:1045–1057. 8. Marchetti P, Hirsch T, Zamzami M, et al. Mitochondrial permeability triggers lymphocyte apoptosis. J Immunol. 1996;157:4830–4836. 9. Renehan AG, Booth C, Potten CS. What is apoptosis, and why is it important? BMJ. 2001;322(7301):1536–1538. 10. Amatya JL, Takeshima Y, Shrestha L, et al. Evaluation of apoptosis and immunohistochemical expression of the apoptosis-related proteins in mesothelioma. Hiroshima J Med Sci. 2010;59(2):27–33. 11. Kandasamy K, Srinivasula SM, Alnemri ES, et al. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome C and Smac/DIABLO release. Cancer Res. 2003;63(7):1712–1721. 12. Watson WH, Cai J, Jones DP. Diet and apoptosis. Annu Rev Nutr. 2000;20:485–505. 13. Krishna S, Low I, Pervaiz S. Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2. Biochem J. 2011;435:545–551. 14. Li XX, Tsoi B, Kurihara H, He RR. Cardiolipin and its different properties in mitophagy and apoptosis. J Histochem Cytochem. 2015;63(5):301–311. 15. Szczepanek K, Lesnefsky EJ, Larner AC. Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. Trends Cell Biol. 2012;22(8):429–437. 16. Witte I, Foerstermann U, Devarajan A, Reddy ST, Horke S. Protectors or traitors: the roles of PON2 and PON3 in atherosclerosis and cancer. J Lipids. 2012;2012:342806. 17. Ray A, Chatterjee S, Mukherjee S, Bhattacharya S. Arsenic trioxide induced indirect and direct inhibition of glutathione reductase leads to apoptosis in rat hepatocytes. Biometals. 2014;27(3):483–494. 18. Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxicol. 1997;16:485–494. 19. Walker PR, Smith C, Youdale T, et al. Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res. 1991;51:1078–1085.

20. Brown DB, Sun XM, Cohen GM. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem. 1993;268:3037–3039. 21. Reynolds ES, Kanz MF, Chicco P, Moslen MT. 1.1-Dichloroethylene: an apoptotic hepatotoxin? Environ Health Perspect. 1984;57:313–320. 22. Aw TY, Nicotera P, Manzo L, Orrenius S. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys. 1990;283:46–50. 23. Rossi AD, Larsson O, Manzo L, et al. Modification of Ca2+ signaling by inorganic mercury in PC12 cells. FASEB. 1993;7:1507–1514. 24. Kunimoto M. Methyl mercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun. 1994;204:310–317. 25. Vivian B, Rossi AD, Chow SC, Nicotera P. Organotin compounds induce calcium overload and apoptosis in PC12 cells. Neurotoxicology. 1995;16:19– 25. 26. Ledda-Columbano GM, Coni P, Curto M, et al. Induction of two different modes of cell death, apoptosis and necrosis in rat liver after a single dose of thioacetamide. Am J Pathol. 1991;139:1099–1109. 27. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Benzene, Draft Report. Atlanta, GA: Department of Health and Human Services. 28. Saha A, Kuzuhara T, Echigo N, Fujii A, et al. Apoptosis of human lung cancer cells by curcumin mediated through up-regulation of “growth arrest and DNA damage inducible genes 45 and 153.” Biol Pharm Bull. 2010;33(8):1291–1299. 29. Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene. 1999;18:3166–3172. 30. Fulda S, Debatin KM. Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol. Cancer Res. 2004;64(1):337–346. 31. Ashkenazi A, Holland P, Eckhardt SG. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol. 2008;26(21):3621–3630. 32. National Institute of Environmental Health Sciences. Sixth Annual Report on Carcinogens. Benzene Case No. 71-43-2:35. Research Triangle Park, NC: National Institute of Environmental Health Sciences 33. Golstein P, Ojcius DM, Ding-E Young J. Cell death mechanisms and the immune system. Immunol Rev. 1991;121:29–65. 34. Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Ann Rev Immunol. 1992;10:267–293. 35. Duke RC, Ojcius DM, Ding-E Young J. Cell suicide in health and disease. Sci Am. 1996;275:80–87. 36. Martin SJ, Green DR. Protease activation during apoptosis: death by a thousand cuts. Cell. 1995;82:349–352. 37. Forrest VJ, Kang Y, McClain DE, et al. Oxidative stress-induced apoptosis prevented by Trolox. Free Radic Biol Med. 1994;16:675–684. 38. Rizza SA, Badley AD. HIV protease inhibitors impact on apoptosis. Med Chem. 2008;4(1):75–79. 39. Schreck R, Meier B, Mannel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kB activation in intact cells. J Exp Med. 1992;175:1181–1194.

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9 Bacterial Overgrowth of the Small Intestine Breath Test Mary James, ND

OUTLINE Introduction, 113 Conditions Associated With Small Intestinal Bacterial Overgrowth, 113 Pathophysiology, 113 Signs and Symptoms, 114 Diagnosis, 115 Endoscopy, 115 Breath Testing, 115

INTRODUCTION Small intestinal bacterial overgrowth (SIBO) is an abnormal colonization within the small bowel by bacteria normally found in the colon, mouth, or pharynx.1 SIBO is a major contributor to irritable bowel syndrome (IBS) and uncomfortable symptoms such as bloating, abdominal discomfort, and changes in the stool (e.g., diarrhea).2 It is also a potentially serious disorder that can lead to problems such as malabsorption and weight loss, anemia, malnutrition,2 increased intestinal permeability,3 and bone loss.4 Breath testing for hydrogen (H2) and methane (CH4) provides a simple, noninvasive means of detecting SIBO. Once SIBO has been identified, antimicrobials are typically administered to eradicate the bacteria. Concurrent attention to underlying causes is also essential in preventing recurrences.

Conditions Associated With Small Intestinal Bacterial Overgrowth SIBO, whose overall prevalence is not yet clear, is an overlooked contributing factor in several common disorders.5 Several studies, for example, have demonstrated the presence of SIBO in patients with IBS.6,7 In one study, in which 84% of patients with IBS tested positive for SIBO (vs. 20% of healthy controls), successful eradication of SIBO led to a 75% improvement (compared with a 36.7% improvement in those with incomplete eradication and an 11% improvement in participants receiving a placebo).8 SIBO has also been observed in patients with acne rosacea,9 Crohn’s disease,10 restless legs syndrome,11 nonalcoholic fatty liver disease,12 interstitial cystitis,13 chronic prostatitis,14 chronic fatigue syndrome,15 and fibromyalgia.16 SIBO may increase intestinal permeability (a.k.a. “leaky gut”),17 an abnormality that was shown in a small study to resolve in 75% of patients successfully treated for SIBO.3 Investigators who found leaky gut in 37.5% of patients with fibromyalgia suggested exposure of immune cells to luminal antigens and consequent immune modulation as a likely mechanism for the pain syndrome.18

Treatment of Sibo, 116 Bacterial Eradication, 116 Antibiotics, 116 Herbal Antibiotics, 116 Antibiotic Alternatives, 117 Addressing the Underlying Causes, 117 Dietary Support, 117

A variety of anatomical and motor disorders of the small bowel can lead to SIBO, including surgical blind loops, diverticula, strictures, adhesions, tumors, fistulas,19 sclerodermas,20 intestinal pseudoobstruction,21 and diabetic enteropathy.22 Jejunal diverticulosis5 and Crohn’s disease23 have both been associated with SIBO, particularly in patients with previous intestinal surgery. Because the symptoms of Crohn’s disease and SIBO can be similar, symptoms from SIBO can be mistaken for a Crohn’s-related acute flare.10 Although the concentration of bacteria normally increases exponentially toward the distal end of the small intestine,19 far fewer bacteria inhabit the small intestine than do the colon.24 A common feature of most of these disorders is stasis of small bowel contents, which allows bacterial concentrations to increasingly resemble those of the large intestine (Box 9.1).24,25 Although many of the bacteria found in SIBO are beneficial within the colon, these same microorganisms can have deleterious effects within the delicate environment of the small intestine. Interestingly, many patients with celiac disease whose symptoms persist despite a gluten-free diet have been shown to have SIBO, with improvement only after bacterial eradication.26 The incidence of SIBO also increases with age.27 It has been found that 64% of individuals more than 75 years of age with chronic diarrhea have colonic-type flora in their small bowels,5 and that SIBO is the most common cause of clinically significant malabsorption in elderly persons.19 

Pathophysiology Two major factors that control the numbers and types of bacteria within the small bowel are intestinal motility and gastric acid secretion.19,24 Accordingly, SIBO has been associated with both intestinal stasis and hypochlorhydria.25 Other factors influencing SIBO include pancreatic enzyme secretion,28 disaccharidase production by microvilli,29 ileocecal valve function,30,84 bile salts, luminal pH, oxidation-reduction potential,24 and migrating motor complex function.31 The migrating motor complex (MMC) is a system of electrical waves that “migrate” throughout the small intestine, serving to propel

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BOX 9.1  Causes of Small Intestinal Bacterial

BOX 9.2  When to Consider Breath Testing

• Achlorhydria, hypochlorhydria, drug-induced hypoacidity • Chronic constipation • Stasis resulting from structural changes (e.g., diverticulosis, blind loops, radiation damage, stricture, fistulas, intestinal pseudo-obstruction, adhesions resulting from prior surgery) • Dysfunctional migrating motor complex • Chronic pancreatic insufficiency • Disaccharidase deficiencies (e.g., lactase) • Dysfunctional ileocecal valve • Immunodeficiency (especially of secretory immunoglobulin A) • Diabetes mellitus • Scleroderma • Crohn’s disease

• Gas, bloating, or diarrhea, usually after eating • Irritable bowel syndrome, either diarrhea or constipation-dependent • Unexplained weight loss • Evidence of malabsorption • Chronic hypochlorhydria or achlorhydria • Use of acid-blocking medications (especially proton-pump inhibitors) • Prior intestinal surgery, chronic constipation, or other causes of intestinal stasis • Intolerance of disaccharides (e.g., lactose) • Unexplained vitamin B12 deficiency, weight loss, or bone loss • Unexplained nutrient insufficiencies (e.g., calcium, magnesium, fat-soluble vitamins) • Unexplained “leaky gut” • Crohn’s disease (especially if history of strictures or small bowel resection) • Restless legs syndrome • Nonalcoholic fatty liver disease • Interstitial cystitis

Overgrowth

luminal contents all the way from the stomach to the terminal ileum over a period of 113 to 230 minutes, depending on the individual.32 The MMC has been referred to as the “intestinal housekeeper.” Its influence on motility is independent of the peristalsis that occurs in the large intestine. For instance, whereas colonic peristalsis is stimulated by eating a meal, the MMC is only active in the fasting state. The MMC consists of four phases. Phase I, which takes place in the stomach, is devoid of contractions. Phase II is composed of lowamplitude, irregular contractions that progress from the stomach to the small intestine. Phase III, initiating in either the stomach or the small intestine, is the most active phase of the MMC; contractions are of high amplitude and travel the length of the small bowel, serving to cleanse it of food from a recent meal. Phase IV represents a brief transition period back to phase I.31,32 MMC dysfunction has been demonstrated in many individuals with SIBO, especially in Phase III.33 For SIBO to produce clinical consequences, an adequate concentration of organisms with particular metabolic properties within specific locations of the small intestine is required. For example, a heavy concentration of strict anaerobes and coliforms in the proximal small intestine is more likely to be associated with malabsorption than a flora consisting of fewer strict anaerobes or coliforms or when strict anaerobes or coliforms are confined to the distal small intestine.24 For this reason, SIBO may be asymptomatic in some individuals yet produce signs and symptoms in others. Box 9.2 outlines clinical signs and symptoms that should alert the practitioner to consider testing for SIBO. 

for Small Intestinal Bacterial Overgrowth

BOX 9.3  Signs and Symptoms of Bacterial

Overgrowth

• Gas, bloating, and flatulence • Diarrhea or constipation • Abdominal cramping • Steatorrhea • Lactose intolerance • Megaloblastic anemia

Signs and Symptoms The classic SIBO syndrome is characterized by megaloblastic anemia resulting from vitamin B12 deficiency and weight loss and diarrhea secondary to fat malabsorption.24 However, many patients present with nonspecific symptoms 1 to 2 hours after a meal, including bloating, flatulence, and abdominal pain resulting from bacterial fermentation of intraluminal sugars and associated gas production, and constipationpredominant SIBO is also possible (Box 9.3).15,26 Via secretory and osmotic processes, diarrhea may occur even in the absence of significant steatorrhea. Unabsorbed fats and bile salts are modified by bacteria in the colon to hydroxylated fats and free bile acids, respectively, which stimulate colonic secretion of water and electrolytes.24 Bile salts, essential to fat emulsification and assimilation, must be conjugated with taurine or glycine to function properly. In SIBO, bacteria in the proximal small intestine can deconjugate bile salts to form free bile acids.24 This can have two major clinical repercussions:

Fig. 9.1 In small intestinal bacterial overgrowth, free bile acids can damage the brush border, resulting in reduced enzyme activity and maldigestion. (Courtesy of Genova Diagnostics, Asheville, NC.)

(1) free bile acids can promote mucosal damage (Fig. 9.1), resulting in reduced brush-border enzyme activities (especially lactase),34 defects in mucosal uptake of sugars and amino acids, enteric blood loss, and protein-losing enteropathy; or (2) the conjugated bile salt

CHAPTER 9 

Bacterial Overgrowth of the Small Intestine Breath Test

concentration may fall below the concentration necessary for effective micelle formation, resulting in fat malabsorption, steatorrhea,24,25 and deficiencies of fat-soluble vitamins.2 Fat malabsorption in SIBO can also result from mechanical interference, specifically the formation of a pseudomembrane, thought to represent a maladaptive defense mechanism against the bacterial overgrowth.35 Unabsorbed fatty acids can form insoluble soaps with calcium and magnesium, rendering them unavailable.2 Osteomalacia, night blindness, hypocalcemic tetany,19 or metabolic bone disease4 may develop as a consequence of lipid malabsorption in patients with SIBO. Although rare, iron-deficiency anemia may result from blood loss2 or possibly from an inflammation-induced upregulation of hepcidin, the body’s main iron-regulating hormone.36 SIBO may also lead to vitamin B12 deficiency, with megaloblastic anemia and low serum cobalamin levels.19,24 Although intrinsic factor is not altered by anaerobic bacteria, microbes are capable of detaching vitamin B12 from the intrinsic factor, as well as directly using B12.30 Either mechanism can make the vitamin unavailable. Paradoxically, serum folate values are usually normal or even elevated in SIBO, a result of the bacterial synthesis of the vitamin.37 Hypoproteinemia may also occur in SIBO, secondary to proteinlosing enteropathy and protein malabsorption.2,25 In addition, bacteria may metabolize proteins to ammonia and fatty acids, thereby rendering them unavailable to the host.34  The composition of bacterial populations contaminating the small bowel is complex and variable.19 However, the diagnosis of SIBO tends to be oriented less to the identification of specific microorganisms and more to overall bacterial concentrations.19

DIAGNOSIS Endoscopy Culture of a small bowel aspirate (typically jejunal or duodenal) via endoscopy is a direct method for diagnosing SIBO; abnormally high bacterial counts confirm the diagnosis.25 Although this technique has been considered the gold standard for diagnosing SIBO, intubation methods are invasive, time-consuming, uncomfortable, and expensive. It also has several shortcomings: (1) because the aspirate is typically taken from only one location, SIBO in the more distal end of the small bowel or concentrated in a large diverticulum or blind loop may be missed38; (2) false positives can result from bacterial contamination from the mouth or esophagus39; and (3) the traditional threshold of >105 cfu/mL is not well validated and may only be appropriate for patients with blind loop syndrome as a result of past surgeries (e.g., Billroth II procedure). It is now generally agreed that a lower cutoff of 103 cfu/mL is sufficient for a diagnosis of SIBO.40,41 

Breath Testing Breath tests were devised as less invasive alternatives to intubation and culture, offering greater patient comfort and convenience. They also offer good sensitivity42: a meta-analysis of 12 studies found that lactulose and glucose hydrogen breath testing identified SIBO in 54% and 31% of patients with IBS, respectively, compared with only 4% of the patients via jejunal aspirate and culture.43 Breath tests are based on the ability of intestinal microbes to ferment carbohydrates, producing H2 or CH4 in the process. A fraction of these gases naturally diffuses from the bowel to the circulation and is excreted with expired air. Because there is no other metabolic source of H2 and CH4, pulmonary excretion of these gases is used as a measure of bacterial fermentation during the passage through the bowel.44

115

Breath tests for SIBO commonly employ either lactulose or glucose, a prescribed dose of which is ingested following 1 to 2 days of dietary fiber restriction and a 12-hour fast.45 In all cases, intestinal bacteria modify the challenge substance, producing an early peak in breath gas values in patients with SIBO. Lactulose is a synthetic, nonabsorbed disaccharide that offers the advantage of traveling the full length of the small intestine. An early H2 (and/ or CH4) peak is typically followed by a prolonged gas peak representing colonic bacterial activity (approximately 90 minutes into the collection process).42,46 Glucose, an absorbable monosaccharide, is not suitable for patients with blood sugar disorders such as diabetes, and its rapid absorption reduces the test’s sensitivity in the distal ileum.42 However, its superior diagnostic accuracy in some studies has led to a growing consensus in favor of glucose over lactulose.47 Differences in methodology between studies may have contributed to the wide range of sensitivities and specificities for lactulose versus glucose (e.g., 31% to 68% and 44% to 100%, respectively, for lactulose; vs. 20% to 93% and 30% to 86%, respectively, for glucose).41 During a breath test, breath specimens are collected by exhaling into a special mouthpiece connected to a vacuum-sealed collection tube. A fasting (prechallenge) breath specimen is collected, a specified amount of lactulose or glucose is ingested, and then nine more breath specimens are typically collected at timed intervals every 15 to 20 minutes. Breath levels of H2 and CH4 are plotted over time, with earlier rises in breath gas values corresponding to more proximal portions of the small intestine. CO2 is also measured because insufficient amounts of CO2 will invalidate results for H2 and CH4.

Hydrogen Versus Methane Versus Hydrogen Sulfide Many studies using carbohydrate challenges have measured only breath H2. However, 30% to 50% of H2 producers also produce CH4,48 most likely a result of “methanogenic” bacteria, which consume H2, producing CH4 in the process.45 Individuals whose intestines harbor methanogenic bacteria typically produce greater amounts of breath CH4 during the test, thus being potentially missed on a test measuring only H2.49 Because of the lack of consistency and standardization across studies, clinics, and practitioners, a North American group of clinician scientists met for discussion in May 2015.40 Consensus was reached that CH4 should be measured along with H2, especially in cases of constipation or slow transit time. Some individuals with SIBO also appear to produce hydrogen sulfide (H2S), a result of intestinal sulfate-reducing bacteria utilizing H2 equivalents such as acetate and formate. H2S is not apparent on the standard breath test measuring H2 and CH4, and in such a case, the breath gases values may form a flat line. Currently available gas chromatography equipment cannot detect H2S. However, a preliminary study examining breath H2S offers promise in diagnosing H2-negative individuals with SIBO.50 Clinical correlations have been noted between various disorders and the production of H2 versus CH4. In one study, individuals producing higher amounts of H2 relative to CH4 reported significantly increased bloating and cramping after carbohydrate ingestion, whereas individuals producing high CH4 reported no significant increase in these symptoms.51 Specific IBS symptoms also vary with breath gas values. For example, CH4 production has been associated more with constipation-predominant IBS, whereas H2 production tends to be more associated with diarrhea.52 SIBO, in general, appears to be more common in diarrhea-predominant IBS than in constipation-predominant IBS.43 

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SECTION 2 

Primary and Adjunctive Diagnostic Procedures

Interpretation of Breath Testing Lactulose is normally not fermented until it reaches the bacteria-rich colon. As a result, the typical fasting breath sample contains less than 20 ppm of H2 or CH4. An increase in breath gas levels in the later breath specimens (90 and 120 minutes) usually reflects colonic bacterial fermentation and is considered normal. Lack of the expected colonic peak can result from antibiotics or an acidic colonic pH.53,54 In patients with SIBO, the lactulose is typically fermented in the small intestine, resulting in an early peak in breath gas values.42 According to the consensus meeting for SIBO in May 2015, a positive test result (indicating SIBO) is defined by a rise in H2 of ≥20 ppm above baseline (or a rise in CH4 of ≥10 ppm above baseline), occurring less than 90 minutes after lactulose or glucose ingestion.40 A double-peak is not considered necessary for diagnosis. Elevated baseline values occur in up to one-third of patients with SIBO53 and have been proposed to relate to the fermentation of endogenous brush-border glycoproteins,55 although future studies are needed to confirm the clinical significance of this finding.40 Various factors may interfere with the breath test, resulting in false-negative or false-positive results. Detailed instructions for breath collection help minimize this interference. False-positive results.  The following factors may account for a false-positive result on a breath test: • Failure to fast for at least 12 hours before the test or to avoid dietary fiber the day before collection can result in excessive “background noise” that contributes to the overall concentration of breath gases.29 • Sleeping, smoking, or eating shortly before or during sample collection can increase concentrations of breath gases.56 • Fermentation by oropharyngeal flora can lead to early, transient elevations in breath gases after carbohydrate ingestion.57 As a result, it is recommended that teeth and tongue brushing be performed before specimen collection.  False-negative results.  False-positive results on a breath test can be caused by the following factors: • Diarrhea or the recent administration of antimicrobials can temporarily reduce the concentration of gut bacteria,58 thus obscuring SIBO. Laxatives and enemas pose a similar risk.59 Patients are advised to wait at least 1 week after antibiotic therapy before performing the test. • SIBO confined to the distal ileum may go undetected if the breath gas peak produced in the ileum merges with the breath gases produced by the colonic flora.42 • Rapid intestinal transit may cause delayed increases in breath gases, leading to a rise only after the lactulose has already reached the cecum.60 This is particularly relevant for patients with SIBO who have undergone small bowel resection. 

TREATMENT OF SIBO For a successful clinical outcome, the treatment of SIBO should not only eradicate the bacterial overgrowth but also address symptoms, underlying causes, and complications of SIBO, such as nutrient deficiencies. Although relapses are common, identifying and treating the individual root causes of SIBO can greatly minimize this potential.

Bacterial Eradication Most patients with clinically significant SIBO host an intestinal flora consisting largely of anaerobes; however, some patients harbor a predominance of gram-negative aerobes, such as Escherichia coli, Klebsiella, and Pseudomonas.61 As a result, the most effective antimicrobial agents are those that target both aerobic and anaerobic microorganisms.19 

Antibiotics According to a meta-analysis of 10 studies using different antibiotics to treat SIBO, antibiotics were superior to placebo in normalizing H2 breath tests (51% efficacy for antibiotics compared with 9.8% for placebo).62 Historically, the first-line antibiotic for SIBO has been tetracycline (250 mg four times daily for 7 days).19 However, the high prevalence of bacterial resistance to this drug (up to 60% of patients with SIBO)19 has led to the use of alternative antibiotics. Common alternatives include metronidazole, clindamycin, neomycin, and rifaximin; amoxicillin, ampicillin, chloramphenicol, erythromycin, ciprofloxacin, and trimethoprim/sulfamethoxazole have been used less frequently.41 The duration of treatment has varied in studies as much as the choice of antibiotic, ranging from 5 days to 1 month. The minimally absorbed and broad-spectrum antibiotic rifaximin is increasingly recognized for its effectiveness and minimum of side effects.63 Rifaximin has been widely studied for its use in functional bowel disorders, including SIBO, and was approved by the U.S. Food and Drug Administration (FDA) in 2015 for diarrhea-predominant IBS. In one study, a 7-day course of rifaximin at 400 mg three times daily normalized breath H2 excretion in 70% of patients with SIBO, whereas tetracycline normalized H2 excretion in only 27% of patients.64 In a larger 7-day study, rifaximin at 400 mg three times daily normalized H2 excretion in 63.4% of patients with SIBO, compared with 43.7% of patients with SIBO taking metronidazole.65 Longer treatment durations of 10 to 14 days are common.63 In cases of excess CH4 production, the addition of neomycin (e.g., 500 mg twice daily) to rifaximin, ideally for 14 days, has been found to be more effective than rifaximin alone.66,67 This is because Methanobrevibacter smithii, the bacterium considered most responsible for CH4 production in the gut, is commonly resistant to many antibiotics. A poor response to antibiotics may indicate mucosal disease, antibiotic resistance, antibiotic-associated diarrhea, or an incorrect diagnosis.30,68 Recurrence of symptoms after treatment suggests the need for follow-up testing and possible retreatment, as well as a closer examination of underlying causes. Older age, history of surgery such as appendectomy, and chronic use of proton-pump inhibitors increase the likelihood of recurrence.69 Because prolonged antibiotic therapy significantly raises the risk of diarrhea, Clostridium difficile infection, and bacterial resistance,19 the administration of probiotics is often advised to minimize such side effects.29 Certain probiotics may also reduce breath H2 in some patients with SIBO.70 However, this is an area of ongoing research in SIBO because probiotics have also been observed to exacerbate symptoms in patients.71 

Herbal Antibiotics Because conventional antibiotics have shown variable success in eradicating SIBO and can come with side effects (most) or a high price tag (rifaximin), interest has been steadily growing in the use of various botanical agents with antimicrobial activity. Small intestinal fungal overgrowth (SIFO) is also present in some patients with SIBO; thus herbal agents may offer the additional advantage of antifungal activity. Anecdotally, some of the more common antimicrobial and/or antifungal herbs used for SIBO include berberine sulfate or berberinecontaining herbs, for example, goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), or goldthread (Coptis chinensis); oregano (Origanum vulgare); allicin (stabilized garlic extract); and neem (Azadirachta indica). In the first formal study examining the efficacy of herbal agents in patients with confirmed SIBO, over a 4-week period, 67 patients received rifaximin and 37 patients received various herbal

CHAPTER 9 

Bacterial Overgrowth of the Small Intestine Breath Test

combinations (totaling 27 herbs) known to have antibacterial and/or antifungal properties.72 At follow-up, 46% of the patients in the herbal therapy group had negative lactulose breath tests, compared with 34% of the patients in the rifaximin group. 

Antibiotic Alternatives Peppermint oil, which has been used successfully in patients with IBS, is a volatile oil with antimicrobial properties.73 Although entericcoated peppermint oil (dose of 0.2 mL three times a day) dramatically reduced gastrointestinal symptoms and reduced breath H2 in a patient with SIBO,74 further research is needed before drawing conclusions about its effectiveness in SIBO. 

Addressing the Underlying Causes Bacterial overgrowth of the small intestine may easily recur if the root causes are not addressed. 

Restoration of Gastric Acidity Because gastric acidity is a critical deterrent to SIBO, restoration of normal stomach pH in patients with hypochlorhydria or achlorhydria is essential. This may include the use of betaine hydrochloride with meals or the discontinuation of antacid medications. A 2017 meta-analysis of 19 studies concluded that the use of proton-pump inhibitors moderately increases the risk of SIBO.75 

Normalization of Intestinal Motility As mentioned, intestinal stasis is a major contributing factor to SIBO. When not a result of anatomical or organic causes, reduced motility may be improved with measures such as increased dietary fiber (especially partially hydrolyzed guar gum, which may be safer in SIBO than other forms of fiber76 and even enhance the effect of rifaximin77), water, probiotics, stress management, and exercise. As stated, impairments in the migrating motor complex (MMC) have been noted in patients with SIBO. The MMC is influenced by both gastrointestinal hormones and the central nervous system. The most active phase of the MMC, Phase III, is induced by serotonin, motilin, and ghrelin. Accordingly, low doses of promotility agents such as serotonin agonists (e.g., tegaserod, prucalopride, or cisapride) and motilin receptor agonists (e.g., azithromycin or erythromycin) are increasingly included in a comprehensive approach to SIBO patients, aimed at preventing relapse71; low-dose naltrexone, an opioid antagonist that interacts with the immune system, is also sometimes employed.78 This is an area of continuing research. In one such study of patients successfully treated for SIBO, tegaserod was shown to dramatically extend

117

symptom-free days posttreatment, and both tegaserod and erythromycin were superior to no prevention at all.79 Abdominal/pelvic adhesions (e.g., from prior surgeries) can sometimes restrict motility in the gastrointestinal tract. Anecdotally, such adhesions may be amenable to visceral manipulation. 

Dietary Support An elemental formula supplies daily nutrition in an easy-to-assimilate form and does not contain carbohydrate residues that can feed bacteria. In a study of 124 patients with IBS with SIBO, an elemental diet was found to normalize lactulose breath tests in 80% of patients after 14 days, a statistic not observed with antibiotics; another five patients achieved a negative breath test after following the diet for an additional 6 days, raising the overall success rate to 85%.80 The precise mechanisms behind the success of an elemental diet are still unclear, although they are postulated to include nutrient deprivation of enteric microbes, stimulation of Phase III of the MMC, and/or stimulation of intestinal immunity.80 Diet is increasingly recognized as a critical factor determining success in the treatment of SIBO. Because bacteria thrive on enteric carbohydrates, restricting dietary fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can theoretically help reduce symptoms and reduce bacterial counts. A systematic review found that a low-FODMAP diet ameliorated IBS symptoms in all FODMAP studies examined.81 Adequate spacing of meals (e.g., at least 4–5 hours apart) is another important therapeutic consideration, based on the fact that the MMC is only active in the fasting state. Patients with SIBO may become lactose intolerant as a result of disaccharidase deficiency. This is often ameliorated with bacterial eradication82; however, temporary avoidance of all disaccharides—the premise of the “specific carbohydrate diet”—can also help “starve” the excess bacteria and allow healing of the intestinal lining.83 Substituting more easily absorbed medium-chain triglycerides for most dietary fat may be helpful in patients with diarrhea and steatorrhea.19 Further research is needed into the role of diet in the treatment and especially the maintenance of remission in SIBO. In the meantime, practitioners continue to experiment and refine various approaches.

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References

51. Kajs TM, Fitzgerald JA, Buckner RY, et al. Influence of a methanogenic flora on the breath H2 and symptom response to ingestion of sorbitol or oat fiber. Am J Gastroenterol. 1997;92:89–94. 52. Pimentel M, Mayer AG, Park S, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci. 2003;48:86–92. 53. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol. 2002;97:1113–1126. 54. Vogelsang H, Ferenci P, Frotz S, et al. Acidic colonic microclimate—possible reason for false negative hydrogen breath tests. Gut. 1988;29:21–26. 55. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterol. 1982;83: 388–393. 56. Solomons N. Evaluation of carbohydrate absorption: the hydrogen breath test in clinical practice. Clin Nutr J. 1984;3:71–78. 57. Thompson DG, O’Brien JD, Hardie JM. Influence of the oropharyngeal microflora on the measurement of exhaled breath hydrogen. Gastroenterol. 1986;91:853–860. 58. Gilat T, Ben Hur H, Gelman-Malachi E, et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut. 1978;19:602–605. 59. Solomons NW, Garcia R, Schneider R, et al. H2 breath tests during diarrhea. Acta Paediatr Scand. 1979;68:171–172. 60. Caride VJ, Prokop EK, Troncale FJ, et al. Scintigraphic determination of small intestinal transit time: comparison with the hydrogen breath technique. Gastroenterol. 1984;86:714–720. 61. Kocoshis SA, Schletewitz K, Lovelace G, Laine RA. Duodenal bile acids among children: keto derivatives and aerobic small bowel bacterial overgrowth. J Pediatr Gastroenterol Nutr. 1987;6:686–696. 62. Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2013;38(8):925–934. 63. Gupta K, Ghuman HS, Handa SV. Review of rifaximin: latest treatment frontier for irritable bowel syndrome mechanism of action and clinical profile. Clin Med Insights Gastroenterol. 2017;10:1179552217728905. 64. Di Stefano M, Malservisi S, Veneto G, et al. Rifaximin versus chlortetracycline in the short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2000;14:551–556. 65. Lauritano EC, Gabrielli M, Scarpellini E, et al. Antibiotic therapy in small intestinal bacterial overgrowth: rifaximin versus metronidazole. Eur Rev Med Pharmacol Sci. 2009;13(2):111–116. 66. Pimentel M, Chang C, Chua KS, et al. Antibiotic treatment of constipation-predominant irritable bowel syndrome. Dig Dis Sci. 2014;59(6): 1278–1285. 67. Low K, Hwang L, Hua J, et al. A combination of rifaximin and neomycin is most effective in treating irritable bowel syndrome patients with methane on lactulose breath test. J Clin Gastroenterol. 2010;44(8):547–550. 68. Bjorneklett A, Hoverstad T, Hovig T. Bacterial overgrowth. Scand J Gastroenterol. 1985;109(suppl):123–132.

69. Lauritano EC, Gabrielli M, Scarpellini E, et al. Small intestinal bacterial overgrowth recurrence after antibiotic therapy. Am J Gastroenterol. 2008;103(8):2031–2035. 70. Gaon D, Garmendia C, Murrielo NO, et al. Effect of Lactobacillus strains (L. casei and L. acidophilus strains cereal) on bacterial overgrowth-related chronic diarrhea. Medicina (Brazil). 2002;62:159–163. 71. Rezaie A, Pimentel M, Rao SS. How to test and treat small intestinal bacterial overgrowth: an evidence-based approach. Curr Gastroenterol Rep. 2016;18(2):8. 72. Chedid V, Dhalla S, Clarke JO, et al. Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Glob Adv Health Med. 2014;3(3):16–24. 73. Shapiro S, Meier A, Guggenheim B. The antimicrobial activity of essential oils and essential oil components towards oral bacteria. Oral Microbiol Immunol. 1994;9:202–208. 74. Logan AC, Beaulne TM. The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Alt Med Rev. 2002;7:410–417. 75. Su T, Lai S, Lee A, et al. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol. 2017;2. [Epub ahead of print]. https://doi.org/10.1007/s00535-017-1371-9. 76. Quartarone G. Role of PHGG as a dietary fiber: a review article. Minerva Gastroenterol Dietol. 2013;59(4):329–340. 77. Furnari M, Parodi A, Gemignani L, et al. Clinical trial: the combination of rifaximin with partially hydrolysed guar gum is more effective than rifaximin alone in eradicating small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2010;32(8):1000–1006. 78. Ploesser J, Weinstock LB, Thomas E. Low dose naltrexone: side effects and efficacy in gastrointestinal disorders. Int J Pharm Compd. 2010;14(2):171–173. 79. Pimentel M, Morales W, Lezcano S, et al. Low-dose nocturnal tegaserod or erythromycin delays symptom recurrence after treatment of irritable bowel syndrome based on presumed bacterial overgrowth. Gastroenterol Hepatol (NY). 2009;5(6):435–442. 80. Pimentel M, Constantino T, Kong Y, et al. A 14-day elemental diet is highly effective in normalizing the lactulose breath test. Dig Dis Sci. 2004;49(1):73–77. 81. Rao SS, Yu S, Fedewa A. Systematic review: dietary fibre and FODMAPrestricted diet in the management of constipation and irritable bowel syndrome. Aliment Pharmacol Ther. 2015;41(12):1256–1270. 82. Nucera C, Lupascu A, Gabrielli M, et al. Sugar intolerance in irritable bowel syndrome: the role of small bowel bacterial overgrowth. Gastroenterol. 2004;126(4 suppl 2):A511. 83. Gottschall E. Breaking the Vicious Cycle. Baltimore: Kirkton Press; 1994. 84. Chander Roland B, Mullin GE, Passi M, et al. A prospective evaluation of ileocecal valve dysfunction and intestinal motility derangements in small intestinal bacterial overgrowth. Dig Dis Sci. 2017;4. [Epub ahead of print]. https://doi.org/10.1007/s10620-017-4726-4.

10 Cell-Signaling Analysis Lise Alschuler, ND, and Aristo Vojdani*, PhD, MSc, CLS

OUTLINE Introduction, 118 The Cell Cycle, 118 Flow Cytometry to Assess Cell-Cycle Status, 119

Clinical Application, 119 Patients Exposed to Carcinogenic Chemicals and Patients With Chronic Fatigue Syndrome, 119

INTRODUCTION

from 2C to 4C. At the end of S, the cell duplicates its genome and now is in the tetraploid state. After the S phase, the cell again enters a phase that was historically thought to be quiescent. Because this phase is the second gap region, it is referred to as G2. In the G2 phase, the cell

Signaling pathways in normal cells consist of growth and control messages from the outer surface deep into the nucleus. In the nucleus, the cell-cycle clock collects different messages, which are used to determine when the cell should divide. Cancer cells often proliferate excessively because genetic mutations cause induction of stimulatory pathways and issue too many “go-ahead” signals, or the inhibitory pathways can no longer control the stimulatory pathways.1 Impressive evidence has now been gathered with regard to the destination of stimulatory and inhibitory pathways in the cell. These pathways converge on a molecular apparatus in the cell nucleus that is often referred to as the cell-cycle clock. The clock is the executive decision maker of the cell; apparently, it runs amok in virtually all types of human cancer. In a normal cell, the clock integrates the mixture of growth-regulating signals received by the cell and decides whether the cell should pass through its life cycle. If the answer is positive, the clock leads the process. 

Cell divides (mitosis) Cell prepares to divide G2

Beginning of the cycle M

G0

Cell enlarges and makes new protein

THE CELL CYCLE A schematic of the classic cell cycle is shown in Fig. 10.1. The cell-cycle compartments are drawn such that their horizontal position reflects their respective DNA content. Cells that contain only one complement of DNA from each parent (2C) are referred to as diploid cells. Cells that have duplicated their genome, and thus have 4C amounts of DNA, are called tetraploid cells. The cell cycle is classically divided into the following phases: • G0 • G1 • S • G2 • M The cell-cycle phase of G1 was historically considered to be a time when diploid (2C) cells had little observable activity. Because this time precedes DNA synthesis, the term Gap 1 (G1) was coined. It is known that there is quite a bit of transcription and protein synthesis during this phase. At a certain point in the cell’s life, the DNA synthetic machinery turns on. This phase of the cell’s life is labeled S for synthesis. As the cell proceeds through this phase, its DNA content increases *Previous edition contributor

118

Cell replicates its DNA

R

S

G1 Restriction point: Cell decides whether to commit to the complete cycle

A

Number of events

G0 + G1

S

B

2C

DNA

G2 + M 4C

FIG. 10.1  Stages of the cell cycle (G0, G1, S, G2, and M phases) (A) and DNA histogram (B) generated by flow cytometry.

CHAPTER 10  produces the necessary proteins that play a major role in cytokinesis. After a highly variable amount of time, the cell enters mitosis (M). DNA content remains constant at 4C until the cell actually divides at the end of telophase. The enlarged parent cell finally reaches the point where it divides in half to produce its two daughters, each of which is endowed with a complete set of chromosomes. The new daughter cells immediately enter G1 and may go through the full cycle again. Alternatively, they may stop cycling temporarily or permanently.2–4 Telomeres, condensed chromatin caps on the ends of chromosomes, dictate the ultimate number of cell divisions that can occur. With each cell division, the telomeres shorten, ultimately to the point that destabilizes the chromosomes sufficiently enough to disallow further mitosis. Thus telomeres are considered to be the “mitotic clock.” Telomere shortening is linked to aging, sedentarism, chronic stress, and age-related diseases, including cancer, coronary artery disease, and heart failure. Cell-proliferation capacity, the cellular environment, and epigenetic factors affect telomere length and therefore cells’ mitotic capacity. Telomere length can be assessed, and a clinical test is available. The telomere length is reported as a telomere score, which is a calculation of the telomere length derived from nucleated white blood cells. This result is then compared with the average telomere length of a similarly aged sample population. Although the transferability of this information to other bodily tissues is not well characterized, telomere length measured in this way has been correlated to clinical outcomes such as cancer incidence and mortality from cancer.5 This information can be used to prioritize interventions that increase telomere length, such as dietary interventions, stress reduction, and antioxidant and vitamin therapies.6 Another influence on the cell-cycle clock is circadian rhythms, or the circadian clock. The circadian clock is the result of molecular clocks in each cell, circadian physiology, and, ultimately, the suprachiasmatic nuclei in the hypothalamus. The circadian clock regulates the activity and expression of proteins related to cell-cycle checkpoints, and in turn these checkpoints regulate circadian-clock proteins. Every cell in the body has circadian-clock proteins, so-called peripheral oscillators, which exert rhythmic control of mitochondrial morphology, energy metabolism, and cell division.7 This has significant clinical implications, particularly in the area of cancer treatment. Both the toxicity and efficacy of cytotoxic agents can vary by more than 50% as a function of when they are dosed in experimental models.8 Although the clinical implications of this have not yet been discovered, the administration of cytotoxic agents in accordance with the circadian-induced activity of the target cells is gaining ground as a reasonable therapeutic approach. 

FLOW CYTOMETRY TO ASSESS CELL-CYCLE STATUS Flow cytometry identifies cells as they “flow” through a detector while being illuminated with intense light. Tissues are generally disaggregated into single-cell suspensions and stained with one or more fluorescent dyes. The cells are forced to flow within a sheath of fluid, eventually being intersected and interrogated by an intense light source, such as a laser beam. As the cell enters the laser beam, it scatters light in all directions. The measurement of light scattered in the forward direction yields information on the particle’s size. Scattered light at right angles to the incident light beam provides information on the internal granularity of the cell. If the cell has been stained with one or more fluorescent dyes, a correlated measurement of more than one cellular parameter can be achieved. The cell cycle is challenging to study because almost any method can cause perturbations to the activity under study. Newer methods to study the cell cycle allow the ability to assess the cell cycle in living cells.

Cell-Signaling Analysis

119

One such method involves labeling the subpopulations of living cells in each phase of the cell cycle with fluorescent proteins. Then, using imaging, one can track and quantify cells in specific phases of the cell cycle using these live cell sensors. This method avoids perturbations to the cell cycle from the test and also allows for the assessment of external influences on the cell cycle.9 

CLINICAL APPLICATION Patients Exposed to Carcinogenic Chemicals and Patients With Chronic Fatigue Syndrome To determine whether peripheral blood lymphocytes (PBLs) isolated from individuals with chronic fatigue syndrome (CFS) and chemically exposed patients represent a discrete block in cell-cycle progression, PBLs isolated from patients with CFS and control individuals were cultured, harvested, fixed, stained with propidium iodide, and analyzed by flow cytometry. The nonapoptotic cell population in PBLs isolated from individuals with CFS consisted of cells arrested in the late S and G2/M boundaries compared with healthy controls. The arrest was characterized by increased S and G2/M phases of the cell cycle (from 9%–33% and from 4%–21%, respectively) (Table 10.1 and Fig. 10.2) at the expense of G0/G1. Such an abnormality in cell-cycle progression indicates abnormal mitotic cell division in patients who have been exposed to chemicals and who have CFS. From these results,

TABLE 10.1  Percentage of Different Phases

of Cell Cycle in Healthy Controls and Patients Exposed to Chemicals Phase

Healthy Controls

Chemically Exposed

G0/G1 S G2/M

88.6 ± 1.4 8.6 ± 1.2 3.6 ± 0.82

51.7 ± 2.4 33.2 ± 4.3 21.0 ± 2.6

3.6 8.6

Cell cycle of health subject 88.6 G0/G1

A

S G2/M 21

Cell cycle of patients exposed to MTBE and benzene

51.7 33.2

B FIG. 10.2 Cell-cycle analysis of peripheral blood lymphocytes from healthy controls (A) and patients exposed to MTBE and benzene (B). Note that in patients’ samples, the majority of cells switched from G0/ G1 to S and G2/M phases.

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it was concluded that the PBLs of patients with chemical exposure and CFS grow inappropriately, not only because the signaling pathways in the cells are perturbed but also because the cell-cycle clock becomes deranged and stimulatory messages become greater than the inhibitory pathways.10,11 However, to limit cell proliferation and avoid cancer, the human body equips cells with certain backup systems that guard against runaway division. One such backup system present in the lymphocytes of patients with CFS provokes the cell to undergo apoptosis. This programmed cell death occurs if some of the cell’s essential

components are deregulated or damaged. For example, injury to chromosomal DNA can trigger apoptosis.1,10,11

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Weinberg RA. How cancer arises. Sci Am. 1996;275:62–70. 2. Wheeless LL, Coon JS, Cox C, et al. Precision of DNA flow cytometry in inter-institutional analyses. Cytometry. 1991;12:405–412. 3. Wersto RP, Liblit RL, Koss LG. Flow cytometric DNA analysis of human solid tumors: a review of the interpretation of DNA histograms. Hum Pathol. 1991;22:1085–1098. 4. Shankey TV, Rabinovitch PS, Bagwell B, et al. Guidelines for implementation of clinical DNA cytometry. Cytometry. 1993;14:472–477. 5. Willeit P, Willeit J, Mayr A, et al. Telomere length and risk of incident cancer and cancer mortality. JAMA. 2010;304(1):69–75. 6. Xu Q, Parks CG, DeRoo LA, et al. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009;89(6):1857–1863. 7. Schmitt K, Grimm A, Dallmann R, et al. Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell Metab. 2018;27(3):657–666.

8. Lévi F, Focan C, Karaboué A, et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev. 2007;59(9– 10):1015–1035. 9. Henderson L, Bortone DS, Lim C, Zambon AC. Classic “broken cell” techniques and newer live cell methods for cell cycle assessment. Am J Physiol Cell Physiol. 2013;304(10):C927–C938. 10. Vojdani A, Ghoneum M, Choppa PC, et al. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med. 1997;242:465–478. 11. Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxicol. 1997;16:485–494.

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11 Erythrocyte Sedimentation Rate Michael T. Murray, ND

OUTLINE Introduction, 121 Erythrocyte Aggregation, 121 Procedures, 121 Westergren Method, 122 Wintrobe Method, 122

Results, 122 Interpretation, 122 Elevated Erythrocyte Sedimentation Rate, 122 Monitoring of Disease Activity, 123 Summary, 124

INTRODUCTION

infectious processes, especially when variables such as anemia confound the ESR. The ESR is also elevated in patients with proteinemias (myeloma, macroglobulinemia, cryoglobulinemia, and cold agglutinin disease).1–4 Disorders of erythrocytes such as various anemias will alter the ESR and may interfere with accurate interpretation.1–4 Because the ESR is directly proportional to the mass of the erythrocyte and inversely proportional to its surface area, large erythrocytes sediment more rapidly than smaller cells. Therefore in macrocytic anemia, there is an increased ESR, and in microcytic anemia, there is a decreased ESR. Although the usefulness of ESR determination has decreased as new methods of evaluating disease have been developed, it remains quite helpful in the diagnosis of some diseases, such as temporal arteritis and polymyalgia rheumatica. Perhaps more useful is its ability to monitor these conditions and others, including chronic inflammatory diseases such as rheumatoid arthritis (RA), Hodgkin disease, and other cancers. Although the use of the ESR as a screening test to identify patients who have serious disease is not supported by the literature, it does provide a general gauge of inflammatory processes in the body. It is well accepted that an extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease, or metastatic malignancy. Recently there has been a growing appreciation of the value of the ESR as a marker for atherosclerosis and coronary artery disease.5,6 In addition, as a sign of chronic low-grade inflammation, it may be helpful as a marker for other conditions as well. For example, in a study of 49,321 Swedish males aged 18 to 20 years, screened for general health and for mental and physical capacity at compulsory conscription examination before military service, there was an inverse correlation between ESR and performance on an IQ test.7 This result indicated that low-grade inflammation, as indicated by the ESR, was associated with reduced cognitive abilities at ages 18 to 20 years. 

The erythrocyte sedimentation rate (ESR), the rate at which erythrocytes settle out of nonclotted blood in 1 hour, has been one of the most widely performed laboratory tests in the past 75 years. Used primarily to detect occult processes and monitor inflammatory conditions, the ESR test has changed little since 1918 when Fahraeus discovered that the erythrocytes of pregnant women sedimented in plasma more rapidly than they did in nonpregnant women. Since its incorporation into standard laboratory diagnosis, the ESR has been shrouded in medical myths and is often misinterpreted or misused. This chapter provides rational guidelines for its use as a nonspecific measure of inflammatory, infectious, neoplastic, and cardiovascular diseases.1–4 

ERYTHROCYTE AGGREGATION Normally, erythrocytes settle quite slowly as the gravitational force of the erythrocyte’s mass is counteracted by the buoyant force of the erythrocyte’s volume. However, when erythrocytes aggregate, they sediment relatively rapidly because the proportional increase in their total mass exceeds the proportional increase in their volume. Therefore the major determinant in the sedimentation rate of erythrocytes is erythrocyte aggregation, which usually occurs along a single axis (rouleaux formation). The aggregation of erythrocytes is largely determined by electrostatic forces. Under normal circumstances, erythrocytes have a negative charge and therefore repel each other. However, many plasma proteins are positively charged and neutralize the surface charge of erythrocytes, thereby reducing repulsive forces and promoting aggregation. The relative contribution of the various “acute-phase” reactant proteins to aggregation is shown in Table 11.1. One protein that has no direct effect on the ESR in physiologic concentrations but is associated with certain inflammatory, degenerative, and neoplastic diseases is C-reactive protein (CRP). Its major function is facilitation of the complement system. Like ESR, the measurement of CRP is used in the monitoring of patients with chronic inflammatory conditions.1,2 An elevated CRP provides evidence of an inflammatory process despite a normal ESR. Therefore, when used in conjunction with the ESR, it greatly increases the sensitivity in detecting inflammatory and/or

PROCEDURES Various methods for determination of the ESR have been developed. Currently, the Westergren method is recommended by the International Committee for Standardization in Hematology.

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TABLE 11.1  Relative Contribution of

Acute-Phase Reactant Proteins to Erythrocyte Aggregation Blood Constituent Fibrinogen β-Globulin α-Globulin Albumin

Relative Contribution 10 5 2 1

BOX 11.1  Results of Westergren and

Wintrobe Methods • Westergren (normal results) • Men: 0 to 10 mm/h • Women: 0 to 15 mm/h • Children: 0 to 10 mm/h • Wintrobe (normal results) • Men: 3000 mg Na/24 h • Salt-restricted diet: 2300 mg Na/24 h (or less) 

INTERPRETATION The results of a Fantus test generally reflect the salt content of the diet. The typical Western diet contains 3.4 g of sodium in a 24-hour period. On a salt-restricted diet, the goal is typically to reduce 24-hour urine sodium to 2.3 g Na/24 h or less. The minimum 24-hour sodium intake considered safe is 0.5 g Na/24 h for healthy individuals with intact adrenocortical function. Some conditions require higher sodium chloride intake (see Table 12.1). A random urine can be tested for urine sodium with the Fantus test and can give an approximation of 24-hour sodium ingestion. A sodium intake of 3.4 g Na/day with an intake of 2750 mL of water from both solids and fluids corresponds to the average water turnover for a 70-kg adult. After evaporation from the lungs and other losses, the amount of water excreted by the kidneys is approximately 1500 mL/24 h.33 A urinary sodium excretion of 3 g in 24 hours would thus produce a urinary sodium concentration of 2 g/L and a urinary sodium chloride concentration of 5.1 g/L (NaCl). A 24-hour urine sample provides a more accurate estimate of 24-hour sodium intake (i.e., 24-hour urine volume × urinary sodium concentration approximates 24-hour sodium intake).

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. DeGowin E, DeGowin RI. New York, NY: Macmillan; 1969:37. 2. Luft FC, Fineberg NS, Sloan RS. Overnight urine collections to estimate sodium intake. Hypertension. 1982;(4):494–498. 3. Taylor WH. Use and interpretation of the Fantus estimation of urinary chloride. Med J. 1951;2(4740):1125–1128. PMID:14869835. 4. Fantus JB. Fluid postoperatively: statistical study. JAMA. 1936;107:14. 5. Marriott H. Water and salt depletion. Br Med J. 1947;1:328. 6. Ambard L, Beaujard E. Causes de l’hypertension arteriole. Arch Gen Med. 1904;1:520–533. 7. Kempner W. Treatment of kidney disease and hypertensive vascular disease with rice diet. III. North Carolina Med J. 1945;6(61–87):117–161. 8. Grohman A, Harrison T, Mason M, et al. Sodium restriction in the diet for hypertension. JAMA. 1945;129:533–537. 9. Chapman CB, Gibbons T, Henschel A. The effect of the rice-fruit diet on the composition of the body. N Engl J Med. 1950;243:899–905. 10. Dustan HP, Bravo EL, Tarazi RC. Volume-dependent essential and steroid hypertension. Am J Cardiol. 1973;31:606–615. 11. Dustan HR, Tarazi RC, Bravo EL. Diuretic and diet treatment of hypertension. Arch Intern Med. 1974;133:1007–1013. 12. Parijs J, Joossens JV, Van der Linden L, et al. Moderate sodium restriction and diuretics in the treatment of hypertension. Am Heart J. 1973;85:22–34. 13. American Heart Association. Changes You Can Make to Manage High Blood Pressure. 2017. 14. Kotchen TA, Kotchen JM. Dietary sodium and blood pressure: interactions with other nutrients. Am J of Clin Nutr. 1997;65(suppl 2):708S–711S. 15. Kurtz T, Morris R. Dietary chloride as a determinant of sodium-dependent hypertension. Science. 1983;222:1139–1141. 16. Sanghavi S, Vassaldotti JA. Dietary sodium: a therapeutic target in the treatment of hypertension and CKD. J Ren Nutr. 2013;23(3):223–227. PMID:23611551. 17. Pizzorno J1, Frassetto LA, Katzinger J. Diet-induced acidosis: is it real and clinically relevant? Br J Nutr. 2010;103(8):1185–1194. 18. Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium Chloride, and Sulfate. Washington, DC: National Academies Press; 2004.

19. Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium Chloride, and Sulfate. Washington, DC: National Academies Press; 2004. 20. Aburto NJ, Das S. Effect of Reduced Sodium Intake on Blood Pressure, Renal Function, Blood Lipids and Other Potential Adverse Effects. Geneva, Switzerland: World Health Organization; 2012. 21. Cogswell ME, Mugavero K, Bowman BA, Frieden TR. Dietary sodium and cardiovascular disease risk- measurement matters. N Engl J Med. 2016;375:580–586. 22. He FJ, Li J, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev. 2013;4:CD004937. 23. Palar K, Sturm R. Potential societal savings from reduced sodium consumption in the U.S. adult population. Am J Health Promot. 2009;24(1):49– 57. 24. Harnack LI, Cogswell ME, Shikany JM, et al. Sources of sodium in U.S. adults from 3 geographic regions. Circulation. 2017;135:1775–1783. 25. U.S. Department of Health and Human Services, U.S. Department of Agriculture. What we eat in America. NHANES. 2013–2014, Table 37.1017. 26. U.S. Department of Health and Human Services, U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 2015. 27. Meneely GR, Batterbee HD. High sodium-low potassium environment and hypertension. Am J Cardiol. 1976;38:768–785. 28. Khairallah P, Sen S, Tarazi R. Angiotensin, protein biosynthesis and cardiovascular hypertrophy (abstr). Am J Cardiol. 1976;37:148. 29. Tobian L, Ishii M, Duke M. Relationship of cytoplasmic granules in renal papillary interstitial cells to “post-salt” hypertension. J Lab Clin Med. 1969;73:309–319. 30. Dahl LK. Effects of chronic excess salt feeding. Induction of self-sustaining hypertension in rats. J Exp Med. 1961;114:231–236. 31. Scribner BH. Salt and hypertension. JAMA. 1983;250:388–389. 32. De Lorenzo F, Hargreaves J, Kakkar VV. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res. 1997;7(4):185–190. PMID: 9292244. 33. Marriott H. Water and salt depletion. Br Med J. 1947;1:328.

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13 Fatty Acid Profiling Patricia M. Devers, DO, and Warren M. Brown, ND

OUTLINE Introduction, 127 Structure and Nomenclature, 127 Measurement, 128 Clinical Significance of Results, 129 Omega-3 (n-3) Polyunsaturated Fatty Acids, 129 Omega-6 (n-6) Polyunsaturated Fatty Acids, 130

INTRODUCTION Dietary fat intake and its emerging role in chronic disease highlight the need for proper fatty acid measurement and profiling. Many studies have implicated fatty acid imbalances in various conditions,1–8 including: • Cardiovascular disease • Chronic inflammatory conditions • Neurological and psychiatric disease • Cancer • Diabetes • Polycystic ovary syndrome • Chronic obstructive pulmonary disease • Asthma Unlike other macronutrients, fat is one of the most difficult dietary intake components to quantify. Patients often misreport their fat intake, and food composition tables are frequently incorrect. There is no single biomarker to assess total dietary fat intake.9 Although the body digests dietary fat into fatty acids, measuring fatty acids cannot validate fat intake because some fatty acids do not come from the diet and are endogenously made. However, there are some biomarkers that reflect essential fatty acid consumption and others that reflect endogenously produced fatty acids. To interpret these measurements, it is important to first understand the definition, physiology, and metabolism of fatty acids. Fatty acids are simple in structure: a carbon backbone with a carboxyl group (COO) at one end and a methyl group (CH3) at the other. They function as energy-storage units, cell membrane structural units, and eicosanoid precursors. Dietary fats are digested into fatty acids, which are then absorbed into the circulation. Three fatty acids can join with glycerol to form triglyceride molecules. Fatty acids are found in serum, cell membranes, and adipocytes. Although there are many fatty acid dietary sources, such as olive oil and fish, some food sources are more critical than others. The term essential fatty acid means these are essential for life and must come from the diet. There are only two essential fatty acids: alpha-linolenic acid (ALA) and linoleic acid (LA). ALA is found in foods such as flax,

Monounsaturated Fatty Acids, 130 Trans Fatty Acids, 131 Saturated Fatty Acids, 131 Fatty Acid Ratios, 132 Summary, 132

chia, walnuts, and unhydrogenated soybean oil.10,11 LA food sources include sunflower seeds, corn oil, and nuts.12 Besides essential dietary fatty acids, there are fatty acids that are made endogenously. The body makes them using three processes: synthesis, elongation, and desaturation. First, fatty acids can be synthesized from acetyl coenzyme A (acetyl-CoA) units made from dietary carbohydrate digestion and metabolism. Insulin’s lipogenic activity allows excess glucose to be converted into triglycerides in the liver. Hence, triglycerides and fatty acids can be made through carbohydrate metabolism.13 Next, fatty acids can be formed using elongase and desaturase enzymes. Some endogenous fatty acids are formed by adding carbons to dietary fatty acid backbones: they are elongated by elongase enzymes. In desaturation, some of the single bonds in the carbon backbone are converted to double bonds. Desaturation enzymes create different fatty acids9,14 (Fig. 13.1). 

STRUCTURE AND NOMENCLATURE As mentioned previously, fatty acids are simple in structure: a carbon backbone with a carboxyl group (COO) at one end and a methyl group (CH4) at the other. The methyl group is labeled omega (ω). When profiling fatty acids, nomenclature can be complex. In general, they are designated based on the length of the carbon atom backbone, the number of double bonds, and the first double bond’s distance from the carbon chain opposite the carboxyl group.9,15 The fatty acid backbone usually ranges between 6 and 22 carbons in length, sometimes longer. Because of the variation in the carbon atom backbone members, fatty acids are categorized as short-chain, medium-chain, long-chain, and very-long-chain fatty acids. Fatty acids are also classified by a double bond’s presence or absence, which determines their saturation degree. Saturated fatty acids have no double bonds. Unsaturated fatty acids have one or more double bonds between carbon atoms. Because fatty acids are necessary for forming cell membranes, saturation can play a role in cell membrane fluidity. Monounsaturated fatty acids (MUFAs), found in olive oil and avocados, have one carbon-carbon double bond, which can occur at

127

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Omega-3 FA α-linolenic Acid (ALA) Stearidonic Acid Eicosatetraenoic Acid Eicosapentaenoic Acid (EPA) Docosapentaenoic Acid Tetracosapentaenoic Acid Tetracosahexaenoic Acid Docosahexaenoic Acid (DHA)

Omega-6 FA

Omega-9 FA

∆ 6 desaturase

Linoleic Acid (LA)

elongase

γ-linoleic Acid (GLA)

elongase

∆ 5 desaturase

Dihomo-γ-linoleic Acid (DGLA)

∆ 5 desaturase

elongase

Arachidonic Acid (AA)

elongase

∆ 6 desaturase

6-oxidation

∆ 6 desaturase

Oleic Acid (OA) Octadecadienoic Acid Eicosadienoic Acid Eicosatrienoic Acid (Mead Acid)

Docodatetraenoic Acid Tetracosatetraenoic Acid Tetracosapentaenoic Acid Docosapentaenoic Acid

Fig. 13.1  Fatty acid metabolism, elongation and desaturation of essential fatty acids. Chang MI, Puder M, Gura KM. The use of fish oil lipid emulsion in the treatment of intestinal failure associated liver disease (IFALD). Nutrients. 2012;4(12):1828 -1850.

different positions within their carbon backbone. The double-bond position designates its name. The most common MUFA is oleic acid, which is found in olive oil. It has a double bond at the ninth carbon and is therefore an omega-9 fatty acid (ω-9). Polyunsaturated fatty acids (PUFAs), found in foods such as salmon and sunflower seeds, contain more than one double bond. In PUFAs, the first double bond may be found between the third and fourth carbon atom from the ω; these are called omega-3 fatty acids (ω-3). If the first double bond is between the sixth and seventh carbon atoms, then they are called omega-6 fatty acids (ω-6).15 It is important to note that some laboratories denote omega using the letter n. For example, omega-3 fatty acids may also be reported as n-3. If the hydrogen atoms on either side of the double bond are in the same configuration, it is termed a cis configuration. Most fatty acids are in the cis configuration. When the hydrogen atoms change configuration, they are considered trans. Trans isomers may be induced during industrial processing of unsaturated oil or found in the gastrointestinal (GI) tracts of ruminant animals (cattle, sheep, goats, and deer). Trans fatty acids produced by industrial processing, such as partially hydrogenated vegetable oil, have been shown to cause endothelial dysfunction and may affect cardiovascular risk factors. Ruminant trans fats, as found in dairy products, may be beneficial.16,17 In fatty acid profiling, it is important to understand this nomenclature because the abbreviations can vary depending on the laboratory used. For example, stearic acid is a saturated fatty acid with 18 carbons and no double bonds (18:0), whereas oleic acid has 18 carbon bonds and one double bond in the n-9 position (18:1n9). Additionally, eicosapentaenoic acid (EPA) has 20 carbons and multiple double bonds and is represented as 20:5n3. This numerical scheme is the systematic nomenclature commonly used by clinical laboratories. It is also possible to describe fatty acid double bonds in relation to the carbon chain’s acidic end, symbolized as delta (Δ). Hence, EPA can also be represented as 20:5 Δ5,8,11,14,17. 

MEASUREMENT Monitoring a patient’s fatty acid status offers a way to target dietary therapeutics and alter disease progression. For this reason, usual or long-term dietary intake markers are important. Fatty acids can be measured as free fatty acids in serum, as erythrocyte membrane components, or in adipose tissue. Adipose tissue fatty acid measurement estimates fatty acid intake ranging from 6 months to 2 years.18 It is therefore the most ideal reflection of dietary patterns. However, adipose tissue biopsy is not practical. Plasma and erythrocyte assessments are more commonly used because of the ease of specimen collection. Because the life of a red blood cell averages 90 to 120 days, erythrocyte fatty acid assessment is more reflective of long-term status and is therefore preferred to plasma evaluation.18 For example, omega-3 plasma levels have been shown to be influenced by an acutely high fish oil dose or a short-term dietary increase.19 Fatty acid biomarkers are sometimes validated by examining the correlation with measured dietary fat intake. Saturated and monounsaturated fatty acid measurements may not always reflect dietary fat intake because these can be endogenously synthesized from carbohydrates.20 Erythrocyte fatty acids are reported as a percentage in the red blood cell (RBC) membrane. When dealing with RBC percentages, one must realize that each fatty acid has an effect on the other percentages. For example, fish oil supplementation (n-3) may increase the overall n-3 percentage, which by default may lower the n-6 percentage. Plasma measurements are expressed as a percentage or absolute total lipid volume concentration. Again, the percentages are interdependent on the whole. After an omega-3 dose, the peak concentration can be observed at 6 hours, whereas the peak percentage can be seen at 24 hours. Plasma-based metrics can be sensitive to fasting status and acute intake. In general, RBC-based metrics are more stable over time.21 

Fatty Acid Profiling

CHAPTER 13 

Stearic 18:0

18

methyl

H3C

trans-Oleic 9t-18:1

H3C

Linoleic (LA) 9c, 12c-18:2 (18:2n–6)

H3C

α-Linolenic (ALA) 9c, 12c, 15c-18:3 (18:3n–3) Arachidonic (AA) 5c, 8c, 11c, 14c-20:4 (20:4n–6)

1 COOH

H3C

cis-Oleic 9c-18:1 (18:1n–9)

129

carboxyl 9

18

H

H

H

18

1 COOH

1 COOH

9 H

18

18

H3C

15

12

9

1 COOH

12

9

1 COOH

20

H3C

Eicosapentaenoic (EPA) 20 5c, 8c, 11c, 14c, 17c-20:5 H3C (20:5n–3)

17

14

11

8

5

1 COOH

14

11

8

5

1 COOH

Docosahexaenoic (DHA) 4c, 7c, 10c, 13c, 16c, 1 19 16 13 10 7 4 22 COOH 19c-22:6 H3C (22:6n–3) Fig. 13.2  Common dietary fatty acids. Structures of some common dietary fatty acids. Ratnayake W, M, N, Galli C: Fat and Fatty Acid Terminology, Methods of Analysis and Fat Digestion and Metabolism: A Background Review Paper. Ann Nutr Metab 2009;55:8–43. https://doi.org/10.1159/000228994

CLINICAL SIGNIFICANCE OF RESULTS See Fig. 13.2.

Omega-3 (n-3) Polyunsaturated Fatty Acids Omega-3 fatty acids are positively correlated with healthy aging throughout life and are essential for brain function and cardiovascular health. The average American diet is deficient in n-3 food sources such as oily fish, nuts, flax, and green leafy vegetables. Deficiencies in n-3 fatty acids can result in neurodevelopmental and behavioral disorders, visual changes, skin abnormalities, and heart disease.22–26 Many studies show that n-3 fatty acids have significantly positive effects on infant development, cancer, cardiovascular disease, depression, attention deficit hyperactivity disorder, and cognitive decline. These health benefits are mediated through several different mechanisms, including alterations in cell membrane composition and function, anti-inflammatory effects, gene expression, and eicosanoid production.27 • Alpha-linoleic acid (ALA) is an essential n-3 fatty acid that must be supplied from the diet. From ALA, other important n-3 fatty acids can be endogenously produced by enzymatic elongation and desaturation. ALA is the 18-carbon, 3-double-bond (18:3n3) precursor to make eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), although these are also found in fish oils. ALA dietary sources include green leafy vegetables, walnuts, chia, hemp, and certain plant oils like flaxseed oil and unhydrogenated soybean oil. Several studies on high dietary intake of ALA and higher ALA blood levels show an association with lower fatal coronary artery disease risk.11 However, there are significant variations in genetics,

nutrition, and toxin load that greatly affect an individual’s ability to make this multistep conversion. • Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with a 20-carbon chain and five cis-double bonds (20:5n3). It can be enzymatically converted from ALA; however, the efficiency of enzymatic conversion is much lower compared with the absorption from EPA-containing foods. EPA can be obtained by eating oily fish such as cod, mackerel, salmon, and sardines. It is also available in fish oil supplements. EPA acts as a precursor for prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3, and leukotriene-5 eicosanoids. EPA has beneficial effects on multiple atherosclerotic and inflammatory processes, including endothelial function, oxidative stress, foam cell formation, inflammatory cytokine production and release, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also reduces atherogenic dyslipidemia and has other beneficial effects arising from its inclusion in membrane phospholipids.28 • Docosapentaenoic acid (DPA) is made by adding carbons to the backbone of EPA using the enzyme delta-5 elongase. It is an intermediary product between EPA and docosahexaenoic acid (DHA) and can retro-convert back to EPA. It is denoted as 22:5n3. Relatively little is known about the potentially distinct DPA health benefits. Although small amounts are found in seafood, it is more often synthesized from EPA.29 • Docosahexaenoic acid (DHA) is a DPA metabolite with 22 carbons and six double bonds (22:6n3). DHA’s endogenous synthesis from its precursor is extremely low, so measured levels largely reflect

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seafood consumption or fish oil supplementation. Fish oil supplementation is commonly a combination of purified EPA and DHA. Cardiovascular disease researchers have studied seafood consumption and fish oil supplementation for both disease prevention and treatment. Fish oil supplementation has been shown to improve serum lipid levels. It prevents cardiac dysrhythmias by increasing cardiac cell membrane fluidity and prevents inflammatory cytokines from binding to their receptors.27 In cardiovascular risk assessment, the Omega-3 Index has emerged as an important biomarker in stratifying patients for targeted therapeutics. The Omega-3 Index is the sum of EPA + DHA percentages in RBCs. A target of >8% is optimal, whereas less than 4% denotes increased cardiovascular risk. Fish oil supplementation and dietary changes using fish, flax, chia, and walnuts are often used as therapeutic interventions. EPA and DHA are also important in fetal brain development. DHA levels positively correlate with the cognitive and retinal development of the fetus.27 Additionally, there is a role for n-3 in cancer prevention. Diets rich in n-3 (fish oil, flaxseed) and high n-3 erythrocyte concentrations are inversely related to colorectal and breast cancer development, likely due to n-3’s anti-inflammatory properties.27 

Omega-6 (n-6) Polyunsaturated Fatty Acids Omega-6 fatty acids play a vital role in many physiological functions. They are particularly important for maintaining bone health, regulating metabolism, and stimulating hair and skin growth. In spite of this, n-6 fatty acids are controversial. The current standard American diet reflects a higher n-6 intake compared with n-3. Dietary sources include vegetable oils and animal fats. Many human evolutionary diets had a 1:1 dietary ratio of n-3:n-6. The fatty acid intake dietary shift toward n-6 sources associated with the cultivation of food and feeding corn to livestock has been implicated in recent increases in disease.30 The issues surrounding n-6 fatty acids include potentially proinflammatory effects, their increased susceptibility to oxidation, and their competition with the n-3 fatty acids for the enzymatic elongation and desaturation pathways. Most of the concern regarding n-6 effects revolves around one of its downstream metabolites: arachidonic acid (AA). AA is the primary precursor in the inflammatory cascade. However, AA is not the only n-6 metabolite, and other n-6 fatty acids can be beneficial. For example, dihomo-gamma linoleic acid (DGLA) is a downstream n-6 fatty acid with many anti-inflammatory benefits. Additionally, linoleic acid has shown significant benefits for cardiovascular risks. • Linoleic acid (LA) is an essential n-6 and denoted as 18:2n6. It is the predominant n-6 in the Western diet, obtained mainly from vegetable oils and nuts. Higher LA intake has been shown to reduce low-density lipoprotein cholesterol, promote insulin sensitivity, and reduce hypertension risk. There is a significant inverse relationship between dietary LA intake and coronary artery disease when using LA to replace dietary carbohydrates and/or saturated fats.12 • Gamma linolenic acid (GLA) is classified as 18:3n6. It can be produced from the essential LA using the enzyme delta-6 desaturase. This is a very slow enzymatic reaction that is further restricted by systemic inflammation, acute and chronic disease, and vitamin and mineral deficiencies such as zinc and cobalt deficiencies.31 However, GLA can be supplemented using black currant, borage oil, and evening primrose. GLA levels are important because GLA is the direct precursor to produce dihomo-gamma linolenic acid (DGLA), which is a highly beneficial and anti-inflammatory n-6. GLA supplementation is rapidly metabolized to form DGLA and therefore is a common therapeutic

intervention.32 However, GLA supplementation can also increase the downstream metabolite AA.8 Supplementing fish oils (EPA/DHA) along with GLA may mitigate this downstream AA conversion because of enzymatic competition for the delta-5-desaturase enzyme. Delta-5desaturase is responsible for both AA production and EPA metabolism. • Dihomo-gamma-linolenic acid (DGLA), 20:3n6, has no significant dietary source (very small amounts can be found in some animal products) and is only metabolized from GLA. Research has confirmed that the inability to convert precursor fatty acids to DGLA is associated with many conditions, including diabetes, cancer, and cardiovascular disease.33 DGLA exerts anti-inflammatory effects when it is metabolized into eicosanoids and prostaglandins. These two oxidative DGLA metabolites have shown clinical efficacy by suppressing chronic inflammation, lowering blood pressure via vasodilation, inhibiting smooth muscle proliferation associated with atherosclerotic plaque development, arresting cancer cell growth, and aiding in tumor cell differentiation.33 • Arachidonic acid (AA), 20:4n6, is a downstream LA metabolite. There are also preformed AA dietary sources, such as animal fats, eggs, poultry, organ meats, and fish. AA is stored in cell membranes and released in response to injury. After AA release, it can be metabolized into eicosanoids through four different pathways: cyclooxygenase, lipoxygenase, cytochrome P450, and oxygen-species–triggered reactions. These pathways yield prostaglandins, isoprostanes, thromboxane, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. Each can act to promote the inflammatory cascade.34 AA-derived eicosanoids have important roles in immunopathology and have been implicated in inflammation, autoimmunity, allergic diseases, and cancer.35 

Monounsaturated Fatty Acids MUFAs are different from other fatty acids because they have only one double bond in their carbon chain. The carbon atom number making up the backbone and the position of this double bond distinguishes one from another and changes their nomenclature. For example, if the double bond is in the seventh position on the carbon backbone, it is known as an omega-7 fatty acid. The most common dietary MUFA sources are olive oil and nuts. Diets rich in MUFAs have shown beneficial effects on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. MUFA diets have been shown to reduce LDL oxidative susceptibility, decrease platelet aggregation, increase fibrinolysis, and increase bleeding time.36 The mechanism involved in MUFAs’ health benefits is still being investigated. However, it has been proposed that changes in the composition of very-low-density lipoprotein (VLDL), VLDL enzymes, and VLDL proteins involved in VLDL catabolism decrease plasma triacylglycerol concentrations. Therefore the rates of VLDL production and triacylglycerol clearance may be altered because of dietary fat type and amount.36 • Oleic acid (OA) has an 18-carbon backbone with one double bond at the ninth carbon. Therefore it is known as an omega-9 fatty acid, 18:1n9. Olive oil is the main source of OA, which is the most represented MUFA in the diet. OA has attracted much attention because of the wide array of literature extolling the “Mediterranean diet,” which is rich in olive oil and nuts. Oleic acid has been shown to reduce saturated fatty acids’ inflammatory effects on endothelial cells due to a dampening of cytokine activation.37,38 • Nervonic acid (NA) is an important omega-9 fatty acid, 24:1n9. NA can be found in small amounts in borage and vegetable oils, but mainly it is an oleic acid elongation product.39 It is abundant in the brain’s white matter and necessary for nerve-cell myelin biosynthesis. NA is essential for brain growth and the maintenance of

CHAPTER 13  peripheral nervous tissue enriched with sphingomyelin.40 Alterations in NA plasma levels have been implicated in mood disorders and demyelinating disorders. Nervonic acid supplementation may also mitigate diabetic neuropathy.41 • Palmitoleic acid (PA) is a monounsaturated omega-7 fatty acid, 16:1n7. The main PA dietary sources are dairy products and macadamia nuts. However, PA can also be synthesized from triglyceride breakdown or de novo from surplus carbohydrates. Dairy products are rich in the trans isomer of PA, whereas macadamia nuts contain the cis isomer. In some studies, the trans isomer from dairy has been associated with less inflammation and lower diabetes risk than other trans fats. PA is involved in insulin sensitivity by exerting distinct effects on insulin signaling and glucose uptake.42 Macadamia nuts are associated with improving lipid profiles. However, whether the lipid-lowering effects are due to PA specifically, or other oils or nutrients found in these nuts, remains uncertain.42 • Vaccenic acid (VA) is a monounsaturated omega-7 fatty acid that is also classified as a trans fatty acid (trans-11-18:1n7). It is a positional and geometric isomer of oleic acid. Unlike trans fatty acids produced industrially, VA is naturally occurring. It is formed when saturated fatty acids are bacterially fermented in the GI tracts of ruminant animals (cattle, sheep, and goats). Dairy products (cheese, milk, butter) and meat from these animals contain VA.43 Although animal and cell studies suggest that VA may be lipid lowering and antiatherogenic, human studies are limited. 

Trans Fatty Acids Trans fatty acids (TFAs) are unsaturated fatty acids with at least one double bond in the trans configuration. There are two primary dietary trans fat sources: naturally occurring TFAs and industrially produced TFAs. Naturally occurring TFAs are consumed in meats and dairy products from cows, sheep, goats and other ruminant animals. As noted previously, these ruminant trans fats are produced through bacterial metabolism in the animal’s GI tract.44 But the more common dietary source in the American diet is industrially formed TFAs, as formed in vegetable oil’s hydrogenation or partial hydrogenation. The hydrogenation process converts vegetable oils into semisolid fats for use in margarines, commercial cooking, and manufacturing processes. These hydrogenated oils are increasingly used to improve grocery shelf life, increase vegetable oil stability during deep frying, and enhance taste in baked goods. The major TFA sources in the American diet are deep-fried fast foods, bakery products, packaged snack foods, and margarines.17 In recent years, TFAs’ dietary implications in public health have received increasing attention. The U.S. Food and Drug Administration (FDA) ruled, effective January 1, 2006, that the nutrition labels for all conventional foods and supplements must indicate trans fatty acid content. This was prompted by the evidence that trans fats promote inflammation and increase coronary heart disease risk. Trans fats also increase triglycerides, increase Lp(a) levels, and reduce LDL particle size.17 • Elaidic acid (EA) is an oleic acid trans isomer (trans-9-18:1). It is the predominant trans fatty acid in the Western diet. EA is found in margarine, partially hydrogenated vegetable oils, and fried foods. EA, like all TFAs, has been extensively studied for its role in increasing cardiovascular risk and adversely affecting lipid profiles. Additionally, EA has recently been shown to enhance metastatic cancer progression.45 • Vaccenic acid (VA), as noted previously, is a monounsaturated omega-7 trans fatty acid. It is formed in ruminant animals’ GI tracts and consumed in the diet as butter, cheese, and meats from

Fatty Acid Profiling

131

these animals. Although, as with all TFAs, increased VA intake and elevated levels increase risk, there is evidence that VA shows some health benefit in rodent and animal studies, although human studies are limited.16 VA’s metabolic fate has not been extensively studied. It is well absorbed from the diet, but from there, it is either rapidly oxidized or metabolized to other lipids. Data are evolving as to whether VA is preferentially oxidized for energy.46 

Saturated Fatty Acids Saturated fatty acids (SFAs) are made up of a carbon chain with no double bonds. Because fatty acids are cell-membrane structural units, this saturated configuration contributes to decreased cell-membrane fluidity. SFAs are not essential nutrients. They are mainly obtained through dietary intake of animal fats. However, the body is capable of synthesizing SFAs from carbohydrates via de novo lipogenesis. The synthesized SFAs are the same FAs found in dietary animal fats. Therefore reducing disease risk using dietary modification should also include carbohydrate reduction. Most saturated fatty acid studies focus solely on their tendency to alter lipoprotein metabolism and influence cholesterol levels. Additionally, several studies have demonstrated that SFAs may cause adipose tissue inflammation. This inflammatory process involves the signaling of toll-like receptor 4 (TLR4), a sensor that binds lipopolysaccharides. This receptor activation signals nuclear factor-kappa B (NFkB) production, which triggers the release of inflammatory cytokines like interleukin 1 and 6 (IL-1, IL-6) and tumor necrosis factor-alpha (TNF-α).47 This inflammatory process is implicated in overall dietary SFA disease risk. • Palmitic acid, or PA (16:0), is a saturated fat naturally found in animal meat and dairy products, as well as in palm and coconut oils. Recent studies reveal evidence that PA excess causes mitochondrial dysfunction mediated by oxidative stress, an effect known as lipotoxicity. Although investigations are ongoing, PA has been linked to an increase in cardiovascular disease risk, cancer risk, and diabetes.48 • Stearic acid (18:0) is found mainly in meat and dairy products. Stearic acid (SA) increases Lp(a) levels, although the effects are less harmful than those of trans fatty acids.49 SA is the only saturated fatty acid with a net neutral effect on serum cholesterol ratios. Although meat is a primary SFA source, not all meat is created equal. Grass-fed beef contains less total fat and tends to contain more conjugated linoleic acid and antioxidants. Grass-fed beef also tends to have much higher cholesterol-neutral stearic acid (18:0) and less cholesterol-elevating SFAs, such as myristic (C14:0) and palmitic (C16:0) FAs.50 Lauric acid (12:0) is a medium-/long-chain fatty acid most often found in coconut oil. Lauric acid’s metabolic and physiological properties account for many of coconut oil’s properties. Lauric acid can be classified as either a medium-chain or long-chain fatty acid. In terms of digestion, however, it behaves more as a long-chain fatty acid because it gets absorbed with chylomicrons. Detailed studies show that most ingested lauric acid is converted directly to energy rather than stored as fat. Most medium-chain fatty acids are absorbed directly into the portal vein and used for energy.51 One of coconut oil’s advantages is its resistance to oxidation and polymerization, which makes it a stable cooking oil. Because of its high SFA content (92%), coconut oil has always been classified, along with butter, palm oil, and animal fats, as a saturated fat source that should be consumed in low levels. Although the common perception remains that saturated fatty acids are bad, an increasing number of researchers contend that medium-chain fatty acids are less hazardous than hydrogenated vegetable oils, such as soybean and corn oils.52 Although lauric

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acid is a saturated fatty acid, there is no link between lauric acid and high cholesterol.53 Infrequent to moderate coconut oil use does not seem to raise cholesterol levels.51,54 

Fatty Acid Ratios Despite the knowledge that fatty acids are implicated in many chronic diseases, there is a fundamental gap in fatty acid research. No accepted established reference ranges define optimal levels. This results in difficulty interpreting results in relation to disease progression and risk. Therefore ratios between specific fatty acids, separately and in groups, are often used.55 • Omega-6/Omega-3 Ratio: As touched on previously, Western diets have changed over the past 100 years. A 1:1 balance (n-6:n-3) existed throughout evolutionary history. The current Western diet averages 15:1 to 16.7:1. The shift to n-6 fatty acids correlates with an increase in many chronic conditions, such as cardiovascular disease, diabetes, cancer, obesity, autoimmune diseases, rheumatoid arthritis, asthma, and depression. The proinflammatory effects of preformed AA, and its formation from n-6 precursors, favors increased thromboxane A2, leukotriene B4, IL-1β, IL-6, TNF-α, and C-reactive protein (CRP). By decreasing n-6 dietary intake and balancing this with increases in flax, walnut, chia, fish, and purified fish oils, these inflammatory effects can be mitigated.55 • Arachidonic Acid/Eicosapentaenoic Acid (AA/EPA) Ratio: EPA, an n-3 fatty acid, metabolically competes with the inflammatory AA to use the same enzyme, delta-5-desaturase, for metabolism. Omega-6 fatty acid dietary intake, specifically animal fats rich in AA, alters essential fatty acid metabolism in favor of inflammation. Adding fish oils, or increasing overall n-3 intake with oily fish, flax, walnut, and chia, shifts delta-5-desaturase activity toward n-3 metabolism and therefore decreases n-6 precursor conversion to AA. Additionally, a decrease in animal fats is helpful.

• Linoleic Acid/Dihomo-Gamma-Linoleic Acid (LA:DGLA) Ratio: The n-6 fatty acid DGLA is anti-inflammatory, and the ability to convert precursor n-6 fatty acids to DGLA is paramount because of its ability to alter disease risk and progression.33 The enzyme responsible for this conversion is delta-6-elongase, which relies heavily on zinc as a cofactor. Delta-6-elongase is quite sensitive to early-stage zinc deficiency. The ratio of LA:DGLA is often used as a zinc status biomarker in humans, in the absence of confounding factors, such as infection or stress. The richest dietary zinc sources include red meats and liver, nuts, seeds, and grains.56

Omega-3 Index The Omega-3 Index was first proposed in 2004 by William S. Harris, PhD, and Clemons von Schacky, MD, as a way of evaluating the risk of death related to coronary artery disease (CAD). It is defined as the RBC percentage sum of EPA + DHA. Estimations show a cardioprotective target to be >8%, and the level associated with increased cardiovascular risk is 1.7 mmol/L). Median triglyceride levels are 2.07, 1.96 and 1.75 mmol/L for the C/C genotype, C/G genotype, and G/G genotype, respectively.66 Conversely, the G allele of the G771C polymorphism is protective against several cardiovascular risk factors.67 The G allele is associated with lower triglyceride levels (−9.86 mg/dL per G allele; OR for hyperlipidemia = 0.73). Furthermore, stronger adherence to a Mediterranean diet enhances the triglyceride-lowering effect of the G allele (OR = 0.63), and this protection is attenuated when the adherence is low (OR = 0.88). The Mediterranean diet also significantly lowered the risk of cardiovascular pathology in carriers of the G allele more so than in C/C homozygotes on the same diet (hazard ratio = 0.34) and compared with carriers of the G allele who were not on the Mediterranean diet (whose hazard ratio = 0.90).68

CHAPTER 15 

Genomics, Nutrigenomics, and the Promise of Personalized Medicine

The SERPINE1 gene (formerly known as PAI-1) codes for plasminogen activator inhibitor-1. This protein is a member of the serpin family and inhibits both the tissue-type and urokinase-type plasminogen activators. Plasminogen activators are responsible for the conversion of plasminogen to plasmin, which, in turn, degrades fibrin. Thus plasminogen activator inhibitor-1 appears to play a major role in determining the proliferative response to vascular injury by inhibiting the degradation of fibrin and several extracellular matrix proteins by plasmin. A SNP in the SERPINE1 gene called the rs6950982 polymorphism is associated with higher levels of several lipids in the blood. People who carry the G allele have higher total cholesterol (A/A: 208, A/G: 210, G/G: 218 mg/dL), higher LDL cholesterol (A/A: 127, A/G: 131, G/G: 136 mg/dL), and higher triglycerides (A/A: 131, A/G: 128, G/G: 154 mg/dL) in the blood. Additionally, men who carry the G allele have higher systolic blood pressure (A/A + A/G: 141.4 mm Hg vs. G/G: 149.8 mm Hg) and diastolic blood pressure (A/A: 81.5, A/G: 82.1, G/G: 85.7 mm Hg). Both men and women with the G/G genotype respond well to the Mediterranean diet for controlling triglyceride levels (∼175 mg/dL in the lower-adherence group vs. ∼125 mg/dL in the higher-­ adherence group).69 

147

DHFR dietary folate

DHF

THF

MTHFD1 purine synthesis

5.10-methylene THF MTHFR 5.10-methyl THF MTRR methionine MAT SAM

Electrolytes and Hypertension Hypertension is an independent risk factor for coronary artery disease and for stroke. The therapeutic response to sodium restriction in hypertensive individuals is highly variable. A SNP in the angiotensinogen gene (AGT) allows an amino acid substitution in which threonine (T) replaces methionine (M) at amino acid 235. The T allele is associated with increased production of angiotensin, with a tendency for higher blood pressure. There is a stepwise increase of serum AGT from MM to MT to TT genotypes among persons with hypertension70 and those with normal blood pressure.71 Although there have been some discrepancies between studies, a meta-analysis of all studies published between 1992 and 1996 showed the 235T allele had a consistent, mild association with hypertension (OR = 1.20), a positive family history of hypertension (OR = 1.42), and more severe hypertension (OR = 1.34).72 A more recent study (2016) puts the risk of hypertension in carriers of two copies of the 235T allele at an OR of 1.8.73 The 235T allele of the AGT gene is associated with greater blood pressure decreases than the 235M allele after an intervention to reduce sodium intake (>5 mg/day).74 Persons with the TT and MT genotypes showed significant systolic blood pressure reductions when consuming mineral salt compared with control subjects (P < 0.02 and P < 0.001, respectively), but persons with the MM genotype did not (P < 0.10). The net adjusted systolic and diastolic blood pressure reduction was –8.6 mm Hg systolic/–3.9 mm Hg diastolic for persons with the TT genotype, –9.0/–5.2 mm Hg for those with the MT genotype, and –5.3/–1.0 mm Hg for the MM genotype. Aerobic exercise was effective in reducing blood pressure but only in the MM (–3.7 mm Hg) and MT (–3.4 mm Hg) genotypes, and not in the TT (–0.4 mm Hg) individuals, among 477 previously sedentary white Americans.75 Finally, the use of angiotensin-converting enzyme inhibitors produced more dramatic reductions in blood pressure in 235T allele carriers (TT and MT) than in the MM genotype,76,77 illustrating the notion that diverse modifications in “environment” (diet, exercise, targeted pharmaceuticals) may produce similar alterations in phenotype (in this case, blood pressure) among genetically susceptible individuals. 

Homocysteine and Micronutrients As mentioned previously, one common physiological effect of SNPs is a decreased binding affinity of a vitamin or mineral coenzyme for the

methylation of downstream targets, e.g. DNA

SAH

SAH hydrolase homocysteine Fig. 15.3  Schematic of the folic acid metabolic cycle. (From Spellicy CJ, Kosten TR, Hamon SC, et al. The MTHFR C677T variant is associated with responsiveness to disulfiram treatment for cocaine dependency. Front. Psychiatr. 2013;3:109. PubMed PMID: 233335901.)

structurally altered enzyme. There is mounting evidence that in most cases, the diminished rate of reaction of that polymorphic enzyme can increase with high-dose cofactor micronutrient supplementation.78 Perhaps the best-studied example of this model is the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), which is responsible for remethylating homocysteine into methionine, allowing methylation reactions to occur efficiently in the body. When methylation reactions are impaired, plasma homocysteine levels rise (Fig. 15.3). Elevated homocysteine values have been associated with an increased risk of atherosclerosis,79 risk of early coronary artery disease,80,81 increased risk of hemostasis and venous thrombosis,82,83 decreased bone density,84 neural tube defects, spina bifida,85,86 Alzheimer’s disease, macular degeneration, hearing loss,87 and acute leukemia in adults.88 The risk of heart disease increases for heterozygotes as well as for 677T/T homozygotes.89 Folic acid and vitamins B2 (as flavin adenine dinucleotide [FAD]), B6, and B12 are all cofactors in the methylation cycle, and a dietary deficiency of any of these vitamins can result in elevated homocysteine levels. However, elevated homocysteine levels can also result from two common polymorphisms in MTHFR: a 677C-T nucleotide substitution and a 1298A-C nucleotide substitution. Someone with a 677T/T genotype has a 50% reduction in MTHFR enzyme activity, whereas a 1298C/C genotype has a 32% reduction. In one study, approximately 28% of patients with elevated homocysteine did not respond to supplementation with folic acid, vitamin B12, and vitamin B6 because they had the 677T/T genotype

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SECTION 2 

Primary and Adjunctive Diagnostic Procedures

and severely impaired MTHFR activity.90 It is worth noting that the 677C-T polymorphism occurs in the FAD site of MTHFR, suggesting that vitamin B2 supplementation may be a critical component.91 Three rational therapeutic strategies may help resolve elevated homocysteine levels. First is high-dose supplementation of the vitamin cofactors of MTHFR, which relies on the simple logic of the law of mass action in a chemical reaction: higher concentrations of substrates drive the chemical reaction forward. Second, the metabolic products of the MTHFR enzyme, namely, 5-methyltetrahydrofolate, may be supplemented. Third, alternate remethylation pathways may be stimulated by supplementing trimethylglycine or betaine as alternate methyl-group donors. Considering the low cost and high degree of safety associated with each of these options, all three strategies may be employed simultaneously. Regardless, serial plasma homocysteine measurements allow the practitioner to determine whether the therapy employed has been successful. Although the science of nutrigenomics is still in its infancy, several principles have become clear, with an enormous potential impact for clinical medicine. Nutrients act as dietary signals that alter gene expression (nutrigenomics). In individuals with specific polymorphisms, their specific genetic variation may render that individual more or less sensitive to specific nutrients or environmental stimuli and, therefore, may help determine optimal diet and lifestyle (nutrigenetics). Knowing the effects of these environmental stimuli on gene expression allows us to use this information proactively to alter gene expression and to mitigate risk for developing various forms of chronic disease, like cardiovascular disease. These principles of nutrigenomics and nutrigenetics hold true for macronutrient balance in the diet and for micronutrients, such as vitamins, minerals, and electrolytes. Although our primary focus here has been on nutrient– gene interactions, the same principles hold true for lifestyle changes and targeted pharmaceuticals. Nutritional intervention is merely a more specific application of environmental modification to alter gene expression. What should be clear is that as our knowledge of gene–gene and gene–environment interactions increases, so too will our capacity for delivery of increasingly personalized and primary prevention. 

GENOMIC TESTING From Early Detection to Prevention We use the term susceptibility gene to refer to a polymorphism that may render an individual more susceptible to the development of a chronic disease when exposed to an adverse environment. Most susceptibility genes have a low positive predictive value (the probability that a disease will develop in a person with a positive test result) and a low attributable risk (the proportion of cases of a disease that can be attributed to a susceptibility gene).92 Therefore some researchers have questioned the clinical utility of susceptibility genetic testing,93 but such arguments, by applying a single-gene/single-disease model to susceptibility genes, miss the clinical relevance. Susceptibility genes, much like taking a family history, must be seen as important but incomplete contributors in what is invariably a multifactorial risk assessment. In terms of health outcomes, preventive genomic polymorphisms raise risk modestly and are additive in their effects (gene–gene interactions), and their actual phenotype expression is strongly affected by diet, lifestyle, and environment (gene–environment interactions). Rather than negate their clinical utility because of a low positive predictive value and a low attributable risk, these polymorphisms begin to offer a molecular basis for understanding the pathophysiology of complex multifactorial diseases, and an understanding of the environmental factors that affect gene expression begins to evoke effective therapeutic strategies.

Because environment is broadly understood to refer to anything outside the genome itself, therapeutic regimens may be constructed to include any portion of the environment that has been shown to affect gene expression and phenotype. This is truly a holistic approach because effective therapeutic strategies may involve diet, nutritional, and targeted pharmaceutical supplementation; lifestyle and behavioral modification; and the avoidance or elimination of toxins, xenobiotics, and microbes. Intervention at any level of our “environment” may prove clinically beneficial. Functional medicine is the clinical discipline designed to promote health, to anticipate and prevent disease, or to correct an existing disease by improving physiological function. The underlying assumption is that health and disease lie on the same continuum, and the connecting thread of the continuum is physiological function. Before the manifestation of any frank disease, a progressive loss of homeostasis and increasing dysfunction occur. Clinical intervention in this strategy may begin at the earliest signs of imbalance.94 The promise of preventive genomics is that the point of effective intervention may begin even earlier, before the beginnings of physiological dysfunction. 

Clinical Challenges Preventive and nutritional genomic testing in clinical practice has its critics, who predominantly argue that there are insufficient numbers of clinical trials to demonstrate the diagnostic and therapeutic efficacy of genomic profiles.95 However, rather than demonstrating that all pregenomic testing is “premature and scientifically unsound,” as suggested by Dr. Muin Khoury of the CDC,96 such objections merely underscore the perspective shared here. Namely, it is precisely because chronic disease is multifactorial with complex gene–gene and gene–environment interactions that the diagnostic and therapeutic utility of preventive genomic testing must meet the four criteria of being relevant, prevalent, modifiable, and measurable. The last criterion, measurable, is critical at this early stage of preventive genomic testing. We must be able to measure beneficial phenotypic, physiological changes in individuals that result from the therapeutic strategy employed. There will always remain a possibility that other genetic polymorphisms or other environmental influences that we have not yet identified may also affect an individual’s disease risk. A similar cautionary argument should be made in cases in which current genomic knowledge offers conflicting therapeutic advice. A man with an Apo-E4 allele presumably should not drink alcohol, but what if he also has a CETP Taq1B polymorphism for which alcohol has been shown to boost HDL cholesterol levels dramatically? At present, the answer is unknown. Fortunately, because fractionated lipid levels are easily measurable, the effects of moderate, daily alcohol intake on such a specific individual’s lipid profile may be easily ascertained. Thus medicine must ultimately be empirical, relying on trial and error until the desired result (e.g., lower serum cholesterol) is achieved. 

Bioethical Considerations: Opportunities and Potential for Discrimination Genetic information, because it represents an unchangeable state, has the potential, at least in theory, to be used in a manner by insurers, employers, and society at large. However, it should be noted that the paradigm for such discrimination views genetic information as representing an individual’s immutable limitations, as typified by single-gene diseases (e.g., Tay-Sachs disease, Huntington’s disease, sickle cell anemia). A fundamental cornerstone of preventive genomics is the idea that the phenotypic outcome of any unique genotype is modifiable through environmental change. Preventive genomic testing, rather than revealing an individual’s genetic limitations, more accurately reflects an

CHAPTER 15 

Genomics, Nutrigenomics, and the Promise of Personalized Medicine

individual’s genetic potential, given the right environment. Genetic polymorphisms have the potential to guide an individual to adopt the appropriate dietary, lifestyle, and environmental changes that can optimize health and longevity. Now that we know there are irrefutable connections between genes and environment, and we are learning their myriad effects on health and disease, ignorance is no longer ethically neutral. Choosing not to use genomic information in treating patients, now that its health implications are being effectively documented, is ethically untenable. For the first time in the history of medicine, preventive genomic testing allows us to assess individual risk for the development of chronic diseases, to develop comprehensive risk-reduction strategies before imbalances in homeostasis occur, and to institute optimal therapy interventions for patients who are already sick. This new personalized medicine, made possible by the advent of preventive genomics and nutrigenomics, offers practitioners and patients new opportunities for the prevention and treatment of disease and for the promotion of optimal health. 

SUMMARY Preventive genomic testing exploring both nutrigenomics and nutrigenetics is both new and exciting. It affords practitioners both novel and effective avenues to develop personalized therapeutic regimens and to promote optimal disease-prevention strategies. Although what we know is dwarfed by what we do not know, this imbalance does not

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negate the current therapeutic power that the past 20 years of genomic research has revealed. We agree with the following assertions made by Loktionov97: • There are many examples of effective research on gene–environment interactions. • There is sufficient evidence to make clinical recommendations on the basis of individualized genomic predisposition. • There is a need for research on traits that protect from, as well as predispose to, disease. • Environment modification, especially dietary changes, may be the easiest and most efficient way to influence the risks of many diseases common today. It is little wonder that Paul Berg, the pioneering researcher in recombinant DNA and genetic engineering and the winner of the Nobel Prize for Chemistry in 1980, once quipped, “At the time, our goal was to focus on the molecular and genetic basis of disease as the starting point for new forms of medicine.”99 However, it is equally true to say that all disease is environmental even when it is also genetic. The symphony between nature and nurture is the very essence of life and health for all creatures who call this Earth their home.

REFERENCES See www.expertconsult.com for a complete list of references.

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16 Hair Mineral Analysis Nick Soloway, LMT, DC, LAc, and Steve Austin*, ND

OUTLINE Introduction, 150 Minerals, 151 Calcium and Magnesium, 151 Chromium, 151 Copper, 151 Manganese, 151 Selenium, 152

Sodium and Potassium, 152 Zinc, 152 Other Minerals, 152 Drug Abuse, 152 Ratios, 152 Discussion, 152

INTRODUCTION

• • • • • • • • • • • • •

Despite many research studies since the original publication of this chapter in 1985, there has been little change in the diagnostic value of hair analysis (HA). Outside its accepted use for monitoring of heavymetal toxicity, at this time HA still has only limited clinical application. In recent years, several attempts have been made to standardize HA testing techniques,1,2 but laboratories still do not have an agreement on procedures for handling a hair sample.3–5,6–8,2,9,10 Many conditions and diseases have been tested for abnormal HA patterns, and a number have been shown to have patterns differing significantly from the norm, including the following: • Learning disabilities11–13 • Birth defects14,15 • Hyperactivity16–18 • Down syndrome19,20 • Neurosis and psychosis21 • Senile dementia22 • Autism23,24,25,26,27 • Alopecia areata28 • Insulin-dependent diabetes mellitus29,30 • Cystic fibrosis31 • Beta-thalassemia32 • Spasticity in children33 • Repeated exposure to radiographs34–36 • Nasopharyngeal cancer37,38 • Aplastic anemia39 • Breast cancer40,41,42 • Bone mineral density43,44 • Type 2 diabetes45 • Alzheimer’s disease46,47 • Hypertension48,49,50,51

* Previous

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edition contributor

 ay fever52 H Atopic dermatitis53 Insulin resistance/metabolic syndrome54,55,56,57,58 Fibromyalgia59 Hemodialysis60 Amblyopia61 Multiple sclerosis62 Cancer63,64,65–68,69,70 Bipolar disease71 Schizophrenia72 Parkinson’s disease73 In vitro fertilization (IVF) pregnancy74 Preeclampsia75 HA has been used successfully to test for drug abuse,76–82,83 and studies have been performed in several locations examining the validity of using HA to test for drug use before the reinstatement of driving licenses.84,85 That said, however, drug metabolites are not found in most commercial hair analyses. HA appears to offer potential as a correlating diagnostic tool in a few of the listed conditions, although the hair mineral patterns should not be used exclusively for diagnosis. For example, the high hair sodium values in infants with cystic fibrosis shows very little overlap with those in controls, and one study demonstrated that children with learning disabilities can be diagnosed with 98% accuracy because of a consistent pattern of high hair values of cadmium, manganese, and chromium in conjunction with low values of lithium and cobalt.11 The usefulness of HA as a research tool hardly can be questioned. However, significant controversy exists about the use of the method for the clinical diagnosis of diseases other than heavy-metal toxicity and as an indicator of nutritional status. Moreover, multiple studies question the interlaboratory and intralaboratory accuracy of HA.86,87,88–90,6-8,2,91 The difference between research and clinical use is significant. Whereas it may be of interest in a research setting that patients with various skin conditions have lower mean levels of hair magnesium than controls, the two groups overlap so much that the procedure is diagnostically

CHAPTER 16  useless.28 Moreover, even when an altered HA pattern has been associated with a disease, generally there are few investigations as to whether mineral supplementation would affect the clinical condition or even revert the hair mineral pattern to normal. Several studies have looked at the relationship between diet and hair mineral status.49,92–96,51 with varying conclusions. Some showed some dietary influences on hair mineral status,93–95,96,97 one showed no correlation,95 and another showed variable correlation.97 Not all hair minerals showed a relationship to intake, and many of the studies had limitations because of a limited time of reporting nutrient intake. Hair grows approximately 1.5 cm per month, so the hair sample usually contains mineral content outside of the nutrient reporting time. Growth rate also varies with ethnicity.98 One study tested hair grown in a 2-year period and found a correlation between low hair Ca, Mg, Sr, and BA and an increased presence of hypertension.51 Gender has been found to result in significant differences in hair minerals,99,100 which can complicate the interpretation of test results. “Levels of elements in the hair are not strictly comparable between different areas of the world.”101 Wide overlap of values in disease and control groups is frequently the case with HA, resulting in excessive false-positive and false-negative results. For example, mentally retarded patients have been found to have hair lead, sodium, and potassium hair values approximately twice those of controls,19 but the standard deviations are extremely large for some minerals (for sodium, 1644.71 ± 1814.93 versus 744.43 ± 198728; and for potassium, 870.15 ± 1009.19 versus 408.35 ± 689.99), and the large overlap greatly reduces the clinical use of HA. In addition, many of the altered HA patterns associated with the diseases previously listed are as yet unconfirmed. 

MINERALS Calcium and Magnesium Hair calcium and magnesium values were found to be elevated in patients with fibromyalgia,102 and another study found decreased levels along with iron and manganese.59 Higher levels of calcium and magnesium were seen in amblyopic children.61 Chronic stress in children had an association with elevated Ca/Mg ratios.103 High hair calcium content has been associated with a reduced risk of coronary heart disease,104 although higher levels were found in hypertensive, obese patients with insulin resistance.49 Higher hair calcium was associated with an enhanced augmentation index, a measure of arterial stiffness.105 Low hair calcium content has been found in the last trimester of pregnancy,106 and hair calcium content increased in response to supplementation during pregnancy.107 Low hair magnesium levels have been reported in autistic children, children with attention deficit hyperactivity disorder, patients with various skin disorders, and patients with several types of leukemia, whereas high levels have been reported in conjunction with dyslexia and Prader– Willi syndrome.18,23,28,108–110 An increase in the Ca/Mg ratio seemed to correlate to increased insulin resistance.55 In contrast, another study saw a decrease in hair calcium and magnesium in metabolic syndrome.56 A decrease in the Ca/Mg ratio was seen in Parkinson’s disease.73 The meaning of these associations remains unknown for the most part, and contrasting findings make interpretation and usefulness questionable. A 2001 study concluded that analysis of hair calcium and phosphorus content was of value as a complementary detection tool in abnormalities of bone metabolism.111 Elevations in both calcium and magnesium were correlated with a low dietary calcium/magnesium ratio in one study, suggesting that this finding may be indicative of an induced hyperparathyroidism,112 but that hypothesis remains unproven. Hair calcium and magnesium also vary in

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response to the hardness and pH of the water in which the hair is usually washed.104 Water consumption from different sources was reported to change hair calcium and magnesium levels; higher hair levels correlated to an increased risk of kidney stone formation.113 Supplementation of dietary magnesium has been reported to increase hair magnesium levels in deficient children.114 Nonetheless, in one study of congenital hypomagnesemia, researchers concluded that hair magnesium level was not a useful tool in monitoring mineral status because the values were higher in affected subjects than in subjects who were not deficient.115 A 2013 study showed that a high hair calcium level was associated with low calcium intake and low bone mineral density.44 There is limited evidence to support the use of hair calcium and magnesium measurements in clinical diagnosis at this time. 

Chromium Hair chromium content is low in insulin-dependent diabetics,30 although there is much overlap with normal persons. Increased insulin resistance was associated with lower hair chromium,55,58 Chromium levels decrease with age,32 but the meaning of this change remains unknown. Hair and tissue chromium levels vary greatly during pregnancy, being very high during the first few months of normal pregnancy and subsequently decreasing.116,117 Late in pregnancy, hair chromium content typically becomes low,118 suggesting deficiency.76 However, high hair chromium value in pregnancy is associated with low-birth-weight infants.119 In patients with gestational diabetes, hair chromium content is high early in pregnancy but decreases in late pregnancy.117 Increasing dietary intake of chromium has been linked to increasing hair chromium values,120 but supplemental chromium does not seem to alter hair levels.116,121 Chromium was found to be higher in patients with a fixed orthodontic appliance. The range of amounts was 8.94 ± 13.1 μg, although the mean was stated to be above the 90th percentile.122 Although normal and deficiency ranges should be more clearly defined, hair chromium content appears to have potential future use in clinical settings. However, current knowledge remains inadequate to help clinicians treat patients on the basis of abnormal hair chromium levels alone. 

Copper Oral contraceptive use is associated with decreased hair copper and increased serum copper.123 High hair copper levels are associated with being female, lactation, idiopathic scoliosis, and pregnancy in some but not all studies.124–127 Surprisingly, conditions that affect systemic copper status have been shown not to affect hair levels. Copper deficiency,128 Wilson disease,129,130 and cirrhosis131 do not significantly alter hair copper content. Hair copper levels also vary with geographical location.132 However, fur and liver copper values have been found to correlate in rats,131 and one study reported that supplemental copper raises hair copper levels.133 Hair color also has been found to influence the levels of copper in the hair.127,134 At this time, hair copper measurement appears unreliable for clinical application.124 

Manganese Levels of hair manganese in mothers of infants with congenital malformations and their offspring were significantly lower in one study,14 which suggest that maternal hair manganese levels may be used as an indicator of the risk for malformations. Hair manganese was inversely associated with working memory in children135 but found not to correlate with developmental scores.136 Both nonsignificantly altered137 and normal levels of manganese138 have been

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SECTION 2 

Primary and Adjunctive Diagnostic Procedures

reported in patients with epilepsy.137 Hair manganese values have been reported to be elevated in people with violent behavior, with varying levels of significance.138,139 Manganese was lower in fibromyalgia,59 in children with amblyopia,61 and in rheumatoid arthritis.140 Evidence that manganese supplementation affects behavior does not appear to exist at present. Hair manganese may serve as a useful research tool in the study of altered behavior, but the most promising value of hair manganese may lie in the prediction of congenital malformations. 

Selenium Levels of selenium in well water and hair show good correlation.141 High hair selenium levels are seen in toxicity142,143 and hyperlipidemia,144 and low levels are seen in deficiency.145 Low hair selenium values have been reported in babies with neural tube defects and their mothers.15 Selenium appears to be transferred transplacentally as measured by hair analysis.146 Lower selenium was seen in patients with phenylketonuria,147 cancer,63,67,68 bipolar disease,71 and steatohepatitis.148 Tissue selenium values reflect short-term variations in intake,82 and hair levels of the element rise significantly after supplementation.149,150 As with chromium, insufficient data are currently available to establish reliable norms for measurement of hair selenium values, and the incidence of false-positive and false-negative results remains unknown. Hair selenium measurement shows promise for clinical use when these problems are resolved, although they haven’t been as of this writing. 

Sodium and Potassium It is generally accepted, even by proponents of HA, that hair sodium and potassium do not reflect dietary status. High elevations of hair sodium may be diagnostic in cystic fibrosis31 but require confirmation. A relatively low Na/K ratio has been reported in celiac disease.151 Although many HA advocates cite low hair sodium and potassium as indicative of “adrenal exhaustion,” the only (preliminary) study exploring this subject reported that hair sodium and potassium do not correlate with adrenal function.152 There have not been any subsequent studies. Except for cystic fibrosis, hair sodium and potassium appear to hold little promise for clinical use. 

Zinc Hair zinc levels have received more research attention than any other mineral. Low hair zinc has been associated with zinc deficiency, anorexia nervosa, hyperactivity, gender, age, atherosclerosis, beta-thalassemia, vegetarianism, lung cancer, leukemia, celiac disease, epilepsy in males, epilepsy in general, short stature in childhood, poverty, insulin-dependent diabetes mellitus, neural tube defects, Alzheimer’s disease,46 hypertension,48 atopic dermatitis,153 breast cancer,153 schizophrenia,72 hypertension,154 prostate cancer,67 liver cancer,150 poor growth in children,155 and during pregnancy.17,29,32,108,156–174 It also has been reported in neonates if the time between pregnancies is short.175 High hair zinc was associated with low serum zinc in Kashin–Beck disease.175 Because a few of these conditions have been associated with potential zinc deficiencies and supplemental zinc has been shown to increase hair zinc levels,154 practitioners who use HA often rely on hair zinc as an indicator of zinc status. However, one trial reported that hair zinc levels declined after supplementation.107,156,157,168,176,177 Other factors that affect hair zinc levels also interfere with the clinical use of this tool. Shampooing and dyeing affect hair zinc levels,178 as do the sex of the subject,178–182 age,127 and hair growth rate. Malnourished children have shown both low171,183,184 and high185 hair zinc.

Poor correlations between hair zinc and height,187 weight, and zinc consumption also have been reported,133,179 although one study reported a correlation among hair zinc, weight, and zinc consumption.186 Another study found that obese people of both sexes had higher hair zinc than those of normal weight and that there was a correlation between the degree of obesity and higher hair zinc levels.187 Although low hair zinc levels have been reported in patients with insulin-dependent diabetes mellitus,176 there is generally considerable overlap between cases and controls. To further complicate the picture, in a study of female descendants of noninsulin-dependent (NIDDM) parents, hair zinc was found to be significantly higher compared with women with no family history of NIDDM.188 At this time there is no definitive understanding of the meaning of abnormal hair zinc levels. The hypothesis that high hair zinc levels reflect acute deficiency, whereas low levels indicate chronic deficiency, remains unproven. 

Other Minerals Hair iron was found to correlate positively with serum ferritin189 and other laboratory markers of iron status,190 although the clinical relevance of this finding is unclear.191 Hair lithium has been reported to show a linear response to extradietary sources.13 Low hair levels of lithium also have been reported in conjunction with heart disease, learning disability, and violent behavior.13 However, research findings are far from the point at which hair lithium could be used to help clinicians diagnose or treat these conditions.13 It is suggested that whole-body iodine status can be assessed with HA.192 

DRUG ABUSE HA has been used to detect drugs of abuse and their metabolites when urine tests were negative.76,78 Hair analysis has been used as evidence in a court of law concerning past drug abuse.77 Although there are concerns about the role of HA in testing for drug abuse,193 HA does seem to be a valuable tool in drug screening.79–82,194 As mentioned, drug metabolites and not mineral levels are measured in these trials, and drug metabolites typically are not reported on most commercially available hair analyses. 

RATIOS The experimental documentation for most of the “ideal” ratios that have been published by several HA companies has not been substantiated in the research literature. The Zn/Cu ratio has been reported to be altered in violent patients.139 This ratio was also elevated in survivors of myocardial infarcts.195 Ca/Mg ratios were elevated in insulin resistance55 and stress102 coronary artery calcification.196 Strong correlations between several mineral ratios and atherosclerosis also have been reported197; however, the clinical significance of these ratios is not known. The Mg/Zn ratios helped separate healthy (1/1) subjects in one study.165 

DISCUSSION Hair mineral analysis is conceptually enticing and potentially a valuable clinical tool. However, problems abound with standardization of sampling, handling, and analysis of hair samples.86,87 Additionally, reference values can differ widely,198,199,10,200 and many variables affect the results.201

CHAPTER 16 

BOX 16.1  Factors That Affect Hair Mineral

Composition

• Gender134,99,100,211 • Age134,212,213 • Ethnicity98 • Environment214–216,101,211 • Hair color127,134 • Cold waving • Bleaching • Exogenous contamination104 • Variations in mineral content within a given sample

This is further aggravated by the reporting of different results on the same sample from different laboratories.87,202,90,7 The distribution of elements within the lipid and nonlipid portions of hair and the treatment of the sample before testing may explain these variances.5,203,8 As noted, dietary intakes do not consistently correlate with hair levels, and hair color, sex, age, and other variables appear to significantly affect levels of some minerals. Separate norms for age, gender, and hair color are now being established.127,204,205,99 However, reviews of the literature attempting to establish reference values continue to show a large variance in mean values, standard deviations, and ranges.132,206,57,91 Although many laboratories make nutritional recommendations, there is no basis for the nutritional advice suggested by some laboratories. See Box 16-1. Several studies have concluded a diagnostic value of HA53,64,105,69,192,70 in specific circumstances. However, to date, there haven’t been additional studies validating the results of these studies, which reduces the power of their conclusions. As a result of the gulf between available information on the one hand and the clinical interest of some practitioners on the other, several articles have appeared decrying the misuses of HA.86,87,207–209

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Hambidge208 has said, “There is a wide gulf between the limited and mainly tentative justification for their use on an individual basis and the current exploitation of multielement chemical analysis of human hair.” Klevay and associates210 acknowledge the experimental usefulness of HA but go on to say that “its use in clinical medicine for diagnosis, prognosis, and therapy will remain limited until validation by the standard methods of clinical investigation is achieved.” Steindel and Howanitz209 conclude the following: Physicians and other health care professionals who are considering ordering hair analysis to assess nutritional status or who are basing nutritional counseling or therapy on hair analysis should reconsider this approach unless and until the reliability of hair analysis value is established and evidence becomes available that clinical recommendations based on hair analysis improve patient outcomes. Even though these comments are over a decade old, the conclusions are still pertinent. The accumulated results of several hundreds of studies do not warrant the use of HA as an independent diagnostic tool. The widespread use of speculative diagnostic procedures invites condemnation, especially when the burden of these speculations falls on the pocketbook and psyche of the patient. HA is a valid and useful screening tool for toxic metal exposure (lead, mercury, cadmium, arsenic, and selenium) and drugs of abuse. It has the potential of becoming a clinical tool of considerable use in other areas. The current nonstandardization of laboratory procedures is more likely to hinder this development than to help it.

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17 Heidelberg pH Capsule Gastric Analysis Stephen Barrie, ND, PhD, and Michael T. Murray, ND

OUTLINE Introduction, 154 Physiology of Digestion in the Stomach, 154 Procedure, 154 Equipment, 154 Methods, 155

Interpretation, 155 Clinical Application, 155 Indications, 156 Aging, 156 Conclusion, 156

INTRODUCTION

After gastrin is absorbed into the bloodstream, it is carried to the gastric glands, where it stimulates the parietal cells to produce HCl acid and, to a lesser extent, the chief cells to produce digestive enzymes (such as pepsin and intrinsic factor). With adequate stimulation, the parietal cells increase their production of HCl by as much as eightfold. When the pH of the stomach reaches about 2, the gastrin mechanism becomes blocked, and feedback causes the parietal cells to decrease the production of HCl. This concentration of hydrogen ions (by a factor of 100,000) is an energy-dependent process. Dietary protein is composed of amino acids held together by peptide linkages. Pepsin A, the major gastric protease, cleaves these in the stomach and is most active at pH values of between 2 and 3. It is inactive at a pH of 5 and above. Consequently, to have any significant digestive effect in the stomach, the gastric juices must be acidic. Trypsin (a protein-splitting enzyme secreted by the pancreas) completes the process, yielding amino acids and dipeptides. The biochemical messenger that stimulates this pancreatic secretion is the acidic bolus of food moving from the stomach into the duodenum. 

Proper digestion is a prerequisite for optimum health, and incomplete or disordered digestion can be a major contributor to the development of many diseases. The problem is not only that ingestion of the best nutritional substances may be of little benefit when breakdown and assimilation are inadequate but also that incompletely digested macromolecules can be inappropriately absorbed into the systemic circulation. This process can lead to various immune complex deposition diseases and is now theorized to be an integral part of the etiology of food allergies. Adequate gastric hydrogen chloride (HCl) is also necessary for the protection of the gastrointestinal tract from ingested pathogens and for the maintenance of the intestinal microbiome. Healthy gut flora is known to be important for proper immune function, vitamin absorption, and the prevention of opportunistic infections such as Candida albicans in the gut. The Heidelberg gastric analysis technique was developed to measure the hydrogen ion concentration (pH) of the digestive tract and determine the acid secretory ability of the parietal cells. Its use of radiotelemetry allows the gathering of this important information in a convenient and accurate manner. The Heidelberg pH capsule system had its origin about 50 years ago at Heidelberg University in Germany. In research sponsored by Telefunken, a West German electronics firm, the inventor H. G. Noeller studied gastric acidity in 10,000 people. Since then, about 140 studies, according to a PubMed inquiry, have used the Heidelberg system to investigate various aspects of digestion.1–7 Physicians and researchers now use this technique for measuring the pH of the digestive system. 

PHYSIOLOGY OF DIGESTION IN THE STOMACH The epithelium of the stomach contains many gastric glands. These tubular glands consist of parietal, chief, and mucous cells. The antral portion of the stomach produces the digestive hormone gastrin, the release of which is stimulated by the following: • Vagal nerve stimulation • The physical bulk of the ingested food distending the stomach • Partially digested proteins

154

PROCEDURE Equipment The Heidelberg system consists of the following equipment: • Radiotelemetry capsule—a hard plastic capsule (about 2 cm long × 0.8 cm in diameter) that contains a miniature radio transmitter, a pH sensing device, and a saline-activated battery • Waistband antenna—receives the signal from the capsule and relays it to the receiver • Receiver/recorder—receives and translates the signal. The pH reading is displayed on a meter and recorded by a continuous printer for a permanent record. The receiver also contains a calibration probe used to calibrate each capsule with known pH 1 and 7 solutions. • Heater block—maintains the calibrating solutions at 37°C 

CHAPTER 17 

Methods The test can be conducted in two ways: the tethered capsule repeat challenge and the flow-through method. Each gives different information and has its advantages and disadvantages. For both procedures, the test begins after the patient has fasted (food and liquid) for 8 hours.

Heidelberg pH Capsule Gastric Analysis 7 6 5 pH 4 3

The Tethered Capsule Repeat Challenge

2

In the tethered capsule repeat challenge, the capsule is tethered so that it remains in the stomach while the stomach is challenged by the ingestion of a saturated sodium bicarbonate solution (i.e., baking soda).8 The challenge solution triggers a rise in stomach pH and a subsequent attempt by the parietal cells to reestablish appropriate acidity. The majority of people have a normal initial pH of between 1 and 2.3. Abnormalities of stomach secretions are usually found only after the stomach is challenged. (A more involved protocol can be found in Wright.8) The procedure is as follows: 1. The waistband antenna is fastened around the patient’s waist, and the receiver/recorder is turned on and calibrated. 2. The patient swallows the capsule, which is attached to a 1-m-long, thin cotton thread (a small amount of distilled water is allowed). The pH reading typically starts at 7 and falls toward 1. After about 5 minutes, the capsule reaches the bottom of the stomach (which normally displays a pH of between 1 and 2), and the remaining thread is taped to the cheek to prevent movement of the capsule out of the stomach and into the intestine. 3. If the fasting pH is normal, the patient swallows the first challenge of 5 mL of the alkaline solution. Within 30 seconds, the pH normally rises to 7, and the patient is asked to lie down on his or her left side (to keep the stomach contents in as long as possible). 4. If stomach function is normal and acid is secreted sufficiently in response to the alkali challenge, the pH returns to normal (between 1 and 2) within 20 minutes. 5. The challenge is repeated up to four times, as long as the response time is within 20 minutes. 

1

Flow-Through Capsule In the procedure for the flow-through capsule, the capsule is not tethered to a thread and is allowed to move freely from the stomach into the duodenum and the rest of the small intestine. The proponents of this method claim that this allows measurement of the gastric emptying time and intestinal pH, both of which are important parameters. 

INTERPRETATION Results may be classified as normal, hypochlorhydria, achlorhydria, and hyperchlorhydria. Normal. The patient successfully reacidifies after four challenges (Fig. 17.1). Curve number 1 shows the capsule entering the digestive tract, number 2 shows the capsule reaching the bottom of the stomach and alkaline challenge occurring, and number 3 shows a pH rise after swallow and subsequent reacidification within 20 minutes. Hypochlorhydria. The patient requires more than 20 minutes to reacidify (Fig. 17.2). Curve number 1 shows a pH of 1 being reached after 30 minutes. Note that on the third challenge, the pH comes back only to about 4. Achlorhydria. The patient’s stomach shows little acid secretion and is not able to secrete enough acid to bring the pH below 4, even on the first challenge (Fig. 17.3). The pH remains at about 4.2 for almost 2 hours.

155

30

60

90

120

Minutes Fig. 17.1  Normal Heidelberg gastrogram.

7 6 5 pH 4 3 2 1 30

60 90 120 Minutes Fig. 17.2  Hypochlorhydric gastrogram.

7 6 5 pH 4 3 2 1 90 60 120 Minutes Fig. 17.3  Achlorhydric gastrogram. 30

Hyperchlorhydria. The gastrogram shows extremely rapid reacidification (within 5 minutes) after each challenge. Depending on specific curve components, some investigators believe that mucous quantity, fresh or chronic ulcers, and acute gastritis conditions can sometimes be identified. 

CLINICAL APPLICATION Gastritis, indigestion, heartburn, and symptoms of gastroesophageal reflux can be associated with either HCl deficiency or excess. Proper distinction is important for several obvious reasons. Patients with hypo- or achlorhydria incorrectly treated for hyperacidity via acid-blocking drugs may experience symptom relief but also further deterioration of the intestinal structure, function, and intestinal microbiome. Direct measurement of gastric acid secretion through endoscopy, intubation, and aspiration is uncomfortable and unacceptable to many patients. The Heidelberg pH

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BOX 17.1  Common Symptoms of Low

BOX 17.3  Diseases Associated With Low

• Bloating, belching, burning, and flatulence immediately after meals • A sense of “fullness” after eating • Indigestion, diarrhea, or constipation • Multiple food allergies • Nausea after taking supplements • Itching around the rectum

1. Addison’s disease 2. Asthma 3. Celiac disease 4. Dermatitis herpetiformis 5. Diabetes mellitus 6. Eczema 7. Gallbladder disease 8. Gastric carcinoma 9. Grave’s disease 10. Chronic autoimmune disorders 11. Hepatitis 12. Human immunodeficiency virus/acquired immunodeficiency syndrome 13. Chronic hives 14. Helicobacter pylori infection 15. Lupus erythematosus 16. Myasthenia gravis 17. Osteoporosis 18. Pernicious anemia 19. Psoriasis 20. Rheumatoid arthritis 21. Rosacea 22. Sjögren’s syndrome 23. Thyrotoxicosis 24. Hyperthyroidism and hypothyroidism 25. Vitiligo

Gastric Acidity

Modified from Wright JV. Healing with nutrition. Emmaus, PA: Rodale Press; 1985.

BOX 17.2  Common Signs of Low Gastric

Acidity

• Weak, peeling, and cracked fingernails • Dilated capillaries in the cheeks and nose (in nonalcoholics) • Postadolescent acne • Iron deficiency • Chronic intestinal parasites or abnormal flora • Undigested food in stool • Chronic candidal infections • Upper digestive tract gassiness Modified from Wright JV. Healing with nutrition. Emmaus, PA: Rodale Press; 1985.

capsule system offers a convenient and accurate outpatient testing system to clinicians interested in evaluating functional gastric acid output. HCl, pepsin, and intrinsic factor are directly involved in digestion and contribute to the chemical changes in the intestines that assist in the absorption of many nutritional factors. For example, vitamin B12 absorption requires intrinsic factor, whereas zinc, calcium, and iron are less efficiently assimilated when gastric acidity is low.9–11 

INDICATIONS Many symptoms and signs suggest impaired acid secretory ability, and a number of specific diseases have been found to be associated with achlorhydria and hypochlorhydria (particularly gastric carcinoma and human leukocyte antigen-B8–related autoimmune diseases). These are listed in Boxes 17.1, 17.2, and 17.3.12–23 The presence of Helicobacter pylori is a major factor in both achlorhydria and hypochlorhydria.24,25 H. pylori induce strong inflammatory responses and a transitory hypochlorhydria, which can progress in ∼2% of patients to atrophic gastritis, dysplasia, or gastric adenocarcinoma.

Aging Numerous studies have shown that acid secretory ability decreases with age. Low stomach acidity has been found in more than half of those older than age 60.26,27 One study of the elderly found that their tissue

Gastric Acidity

Data from references 12 through 24.

nutrient levels could be saturated only through the use of intramuscular supplementation; oral supplementation was ineffective. The authors speculated that this was caused by atrophy of various digestive organs.28 

CONCLUSION The Heidelberg pH capsule system is an effective and convenient method to determine gastric acid secretory ability under conditions simulating ingestion of food. The results are extremely valuable in identifying the large number of people who have impaired secretion function. The ramifications of impaired acid secretion are widespread. This technology has become an accepted method of assessing gastric pH in several research settings.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Noeller HG. The use of a radiotransmitter capsule for the measurement of gastric pH. German Medical Monthly. 1961;6:3. 2. Noeller HG. Results of examinations of stomach functions with the endo-radio capsule—a new appliance for assisting stomach diagnosis. Fortschritte der Medizin. 1962;80:351–363. 3. Steinberg WJ, Mina FA, Pick PG. Heidelberg capsule. In vitro evaluation of a new instrument for measuring intragastric pH. J Pharm Sci. 1965;54:772– 778. 4. Stavney LS, Hamilton T, Sircus W. Evaluation of the pH-sensitive telemetry capsule in the estimation of gastric secretory capacity. Am J Dig Dis. 1966;11:753–760. 5. Dabney R, Yarbrough I, McAlhany JC. Evaluation of the Heidelberg capsule method of tubeless gastric analysis. Am J Surg. 1969;117(2):185–192. 6. Andres MR, Bingham JR. Tubeless gastric analysis with a radio-telemetry pill. CMA. 1970;102:1087–1089. 7. Mojaverian P, Ferguson RK, Vlasses PH, et al. Estimation of gastric residence time of the Heidelberg capsule in humans. Gastroenterol. 1985;89:392–397. 8. Wright J. A proposal for standardized challenge testing of gastric acid secretory capacity using the Heidelberg capsule radiotelemetry system. J John Bastyr Coll Nat Med. 1979;1:3–11. 9. Brewer GJ. Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers. J Parent Ent Nutr. 1995;19:393–397. 10. Mahoney AW, Hendricks DG. Role of gastric acid in the utilization of dietary calcium by the rat. Nutr Metab. 1774;16:375–382. 11. Jacobs A, Rhodes J. Gastric factors influencing iron absorption in anaemic patients. Scan J Hematol. 1967;4:105–110. 12. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789. 13. Howitz J, Schwartz M. Vitiligo, achlorhydria, and pernicious anemia. Lancet. 1971:1331–1334.

14. Bray GW. The hypochlorhydria of asthma in childhood. BMJ. 1930:181–197. 15. Hosking DJ, Moody F, Stewart IM, et al. Vagal impairment of gastric secretion in diabetic autonomic neuropathy. BMJ. 1975:588–590. 16. Rabinowitch IM. Achlorhydria and its clinical significance in diabetes mellitus. Am J Dig Dis. 1949;18:322–333. 17. Carper WM, Butler TJ, Kilby JO, et al. Gallstones, gastric secretion and flatulent dyspepsia. Lancet. 1967:413–415. 18. Rawls WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroent. 1950;18:267–271. 19. Gianella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections. Ann Intern Med. 1973;78:271–276. 20. De Witte TJ, Geerdink PJ, Lamers CB. Hypochlorhydria and hypergastrinemia in rheumatoid arthritis. Ann Rheum Dis. 1979;38:14–17. 21. Ryle JA, Barber HW. Gastric analysis in acne rosacea. Lancet. 1920:1195–1196. 22. Ayres S. Gastric secretion in psoriasis, eczema and dermatitis herpetiformis. Arch Derm. 1929;20:854–859. 23. Dotevall G, Walan A. Gastric secretion of acid and intrinsic factor in patients with hyper and hypothyroidism. Acta Med Scand. 1969;186:529–533. 24. Smolka AJ, Backert S. How Helicobacter pylori infection controls gastric acid secretion. J Gastroenterol. 2012;47:609–618. 25. Adamu MA, Weck MN, Gao L. Incidence of chronic atrophic gastritis: systematic review and meta-analysis of follow-up studies. Eur J Epidemiol. 2010;25(7):439–448. 26. Rafsky HA, Weingarten M. A study of the gastric secretory response in the aged. Gastroenterol. 1946;8:348–352. 27. Davies D, James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Brit J Med. 1930:1–14. 28. Baker H, Frank O, Jaslow SP. Oral versus intramuscular vitamin supplementation for hypovitaminosis in the elderly. J Am Geriat Soc. 1980;48:42–45.

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18 Immune Function Assessment Heather Zwickey, PhD, and Brice Thompson, ND, MS

OUTLINE Introduction, 157 Antibodies, 157 Blood, 157 Urine, 161 Cerebrospinal Fluid, 161 Measurement of Complement and High-Sensitivity C-Reactive Protein, 161 Complement, 161

INTRODUCTION Immune physiology involves complex interactions between cells and proteins to mediate an effective response to infectious disease. A healthy immune system eliminates pathogenic microbes while simultaneously creating a biodynamic relationship with normal microflora. Because the immune system must also effectively distinguish between dangerous foreign invaders and self-antigens, immune dysfunction can result in infection, autoimmunity, cancer, allergies, and asthma. Healthy immune function is affected by age, gender, sleep, nutrition, environmental toxins, and exercise. Natural therapies such as herbs, meditation, hydrotherapy, and supplements can also enhance and manipulate immune reactions. A variety of tests can be used to evaluate the immune system. To determine what type of immune assessment to use for each clinical diagnosis, it is important to understand how underlying immune physiology contributes to a clinical picture. Clinicians can assess the qualitative or functional activity of immune cells. Qualitative data may include things like types, number, and activation states of cells. Cells of the immune system express different proteins on their surface. These proteins, called biomarkers, allow identification of different cells as well as their activation state. To assess immunodeficiency and lymphoproliferative diseases, the number of T cells and B cells must be quantified. Analysis of the functional activity of immune cells involves putting the cells into an in vitro assay system; adding antigen or mitogen; and measuring a function such as cytotoxicity, cytokine production, or antibody secretion. The levels of proteins that are produced by lymphocytes and monocytes, such as cytokines and antibodies, can be analyzed as well. Tests of genetic predisposition to disease can be evaluated with genetic tests. An overview of the assays used to measure cells is given in Table 18.1. A description of these tests is provided in Box 18.1. 

ANTIBODIES Blood Antibody (also called immunoglobulin) is a protein made by B cells in response to an antigen. Each B cell has specificity for one antigen.

High-Sensitivity C-Reactive Protein, 161 Measurement of Cells, 162 Lymphocyte Subpopulations, 162 Cytokines, 164 Genetics, 164 Clinical Symptoms, 164 Sickness Behavior, 164 Summary, 164

This specificity is determined by gene rearrangement long before a B cell ever encounters an antigen. The antibody is found both on the surface of B cells and is secreted. B cells are primarily found in the lymph nodes, Peyer’s patches of the gut, and the spleen (80%); however, antibody is readily detectable in the blood and other bodily fluids. Antibodies look like the letter “Y” (Fig. 18.1). Each part of the antibody has a different function: the arms bind specifically to antigen, whereas the base (the Fc region) allows the antibody to bind to receptors. This base region is called the “isotype.” Antibodies come in multiple isotypes based on the constant region of their heavy chain. These different isotypes have functional importance. Some isotypes are better than others at triggering the complement cascade. The Fc receptors of other isotypes allow them to activate specific cells, such as mast cells and eosinophils. Antibodies are essential to measuring immune function because they can act as both an indicator of disease and as a tool to measure the levels of other proteins and cells. Monoclonal antibodies are a powerful tool (see Box 18.2). Measuring serum antibody is essential in patients who have repeated or severe infections. Low antibody levels in these patients may indicate

TABLE 18.1  Overview of Assays to

Measure Specific Immunity Type of Immunity

Assays

Humoral immunity Cellular immunity

Antibody production: ELISA, cytometric bead array Cytokines: ELISA, ELISPOT, cytometric bead array, RIA, intracellular cytokine staining Cytotoxicity: 51 chromium release assay Proliferation: CFSE, lymphocyte proliferation assay SNPs genetic microarray

Genetics

CFSE, Carboxyfluorescein succinimidyl ester; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunosorbent spot; RIA, radioimmunoassay; SNP, single-nucleotide polymorphisms.

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BOX 18.1  Testing Methods ELISA The enzyme-linked immunosorbent assay (ELISA) is an assay used to measure proteins of the immune system. In ELISA, an antigen is fixed to the surface of a 96-well plate, and then a specific antibody is incubated with the antigen so that it forms an immunocomplex. This antibody is linked to an enzyme that allows the antigen to be converted into a detectable signal, most often a change in color. The more antigen that is present, the darker the color.  ELISPOT A variation of the ELISA is the enzyme-linked immunosorbent assay (ELISPOT). Peripheral blood mononuclear cells (PBMCs) are plated on a filter-bottom 96-well plate coated with anticytokine antibody. The plate is cultured for 24 to 48 hours to allow cytokine secretion and capture on the plate. Cells are washed off and detector antibody is added, followed by an enzyme substrate. Cytokine-secreting cells are identified as spots of secreted cytokine. Cytometric Bead Array A cytometric bead array uses multiplexed beads labeled with capture antibodies for specific analytes, such as cytokines or other serum proteins. Serum is added together with Phycoerythrin (PE)-labeled detector antibody. The antibody-antigen complex is run through the flow cytometer, and software calculates the level of each analyte based on PE fluorescence of each bead population relative to a standard curve.  Intracelluar Cytokine Staining The intracellular cytokine-staining technique uses the flow cytometer to ensure production of cytokines in short-term stimulated whole blood or PBMCs before the cytokines are secreted from the cells. One advantage of this assay is that multiple cell-surface and intracellular markers can be analyzed in combination using multiparameter flow cytometry.  Chromium-51 Release Assay To test the ability of CD8 T cells or natural killers (NKs) to kill, target cells are incubated with a radioactive isotope of chromium-51, which can be released when the cell dies. The CD8 T cells or NKs are then placed in serial dilution with the antigen-presenting cells. Antigen is added in the case of the CD8 T cells. When the target cells are killed by the CD8s, the amount of radioactivity or enzyme can be analyzed.  Lymphocyte Proliferation Assay The proliferation capability of T cells can be measured by isolating PBMCs, separating the T cells, and incubating with tritiated thymidine (3H). A mitogen such as lipopolysaccharide is added to the cell culture. This mitogen may induce cell proliferation. As the cells divide, they incorporate the 3H into the DNA, and analysis of radioactivity can determine how many cell divisions occurred. An ELISA may also be performed to measure cytokine production by the CD4 T cell.  Carboxyfluorescein Succinimidyl Ester Carboxyfluorescein succinimidyl ester (CFSE) can be used to measure cell division. In this assay, the parent cell is incubated with CFSE, which is incorporated into DNA during cell division. As the cell divides, each of the daughter cells contains half of the CFSE stain. Every subsequent cell division halves the amount of CFSE in the daughter cells. When these cells are run through a flow cytometer, a characteristic pattern is seen (see Fig. 18.2).

an immunodeficiency. Patients with myelomas and lymphoproliferative disorders may have high antibody levels. For example, patients with alcoholic liver disease often have a polyclonal expansion of immunoglobulin-A (IgA), whereas patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome have polyclonal IgG expansion.1

Fig. 18.1  Molecular structure of a human antibody. (mirror-images/iStock.com)

BOX 18.2  Monoclonal Antibodies One of the primary tools used in many of the assays for immune function is the monoclonal antibody. Monoclonal antibodies are the product of a single B cell. To generate a monoclonal antibody, an antigen is injected into an animal, and the resultant B cells are isolated. These B cells are diluted, and a single B cell is fused with a nonsecreting myeloma cell line to form hybrids. These hybrids then produce the monoclonal antibodies highly specific for the injected antigen. In contrast, when an animal is injected with an antigen, polyclonal antibodies are generated. Many different B cells specific for that antigen release antibody, which is harvested and purified. This collection of antibodies is called polyclonal because, unlike monoclonal antibodies, it has many specificities to the same antigen. Polyclonal and monoclonal antibodies can be tagged with enzymes for fluorescence to detect the original protein antigens for which they are specific.1 Many proteins have monoclonal antibodies specific for them, including cell-surface markers, cytokines, and even other antibodies. The quality of the monoclonal antibody can determine the sensitivity and specificity of the test used.

The type of isotype made by B cells can provide clues as to the immunological status of the patient (Table 18.2). The route and duration of exposure, type of antigen, and genetic background may all affect the isotype of antibody that is produced, as well as the subclass of antibody produced. Upon immediate exposure to a novel infectious organism, the body produces immunoglobulin-M (IgM). After the B cell makes IgM, it class switches to another isotype, as determined by a combination of activation proteins and cytokines. If the patient has been exposed to an infectious agent, the antibody usually will class switch to IgG.

Immunoglobulin-G IgG is the major antibody found in blood, and it consists of four subclasses, originally described in the 1980s according to their abundance

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159

TABLE 18.2  Antibody Function Isotype

Serum Levelsa

IgM IgD IgG

0.5–2.0 Trace

IgE

Subclasses

5.0–12 2.0–6.0 0.5–1.0 0.1–1.0 Trace

IgG1 IgG2 IgG3 IgG4

0.5–3.0 0–0.2

IgA1 IgA2

IgA

Function/Description Secreted during initial infection; makes large antibody–antigen complexes Function unknown Coats microorganisms, making them more likely to be phagocytosed by macrophages, dendritic cells, and neutrophils; neutralizes toxins Responds to protein antigens Primarily responds to polysaccharide antigens; binds poorly to Fc receptors Responds to protein antigens Response to repeated antigenic exposure; binds poorly to Fc receptors Binds to Fc receptors on mast cells/eosinophils and basophils to elicit allergic response; also involved in response to parasites and worms Provides protection at mucosal surfaces Monomeric form found in blood; can trigger inflammation through FcαR1 Dimeric form found in secretions like tears, saliva, and breast milk

Ig, Immunoglobulin. aSerum levels presented in grams per liter.

in serum. IgG1 and IgG2 are present in much higher concentrations than IgG3 and IgG4. All subclasses of IgG are low in pediatric populations. Deficiency in some IgG subclasses results in increased susceptibility to bacterial infections.2 IgG subtypes vary in their ability to activate complement and Fc-receptor binding. IgG3 has a strong affinity for Fc receptors and has the greatest ability to activate complement. The type of antigen can influence the subclass of antibody response. For example, IgG2 antibodies appear to influence polysaccharide antigens, whereas protein antigens and whole bacteria preferentially elicit IgG1.3–5 IgG4 antibodies, found at the lowest concentration in the serum, are generated to repeatedly presented antigens. IgG4-deficient individuals may be more susceptible to pyogenic infections of the respiratory tract. Antibodies against dietary antigens are frequently IgG4. In a community survey of 40 individuals, antifood antibodies to milk, egg, and fish of the IgG4 subclass were found in a significant proportion of a healthy population, indicating that IgG4 antibodies against food antigens cannot serve as markers of atopic disease. Because IgG4 cannot activate complement, it has been hypothesized that it may serve for protective clearance mechanisms and may be a desirable response to dietary antigens.6 IgG1 and IgG2 have also been found for dietary antigens, but the immunological outcome of these subclasses may be food intolerance that is not caused by immunoglobulin-E (IgE)-mediated hypersensitivity.7 A larger discussion of the immune response to food can be found in Chapter 14. Antibodies of each of the IgG subclasses can be detected by a variety of techniques, including radioactive iodine labeling; antigen-coated red cells; immunofluorescence with antigen-coated Sepharose; radioimmunoassay (RIA); and, most commonly, enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies (Fig. 18.2).8 

Immunoglobulin-A IgA can also be made to infectious agents and occurs in two forms, IgA1 and IgA2. IgA in serum predominantly exists in the monomeric form, IgA1. The ratio of IgA1:IgA2 in serum is about 9:1. IgA found in secretions, termed secretory IgA, occurs as dimers. The ratio of IgA1:IgA2 in secretions varies, but it is approximately 6:4 in saliva.9 Because IgA is found at mucosal surfaces and lines the mucosal surface of the gut, it is not uncommon to find IgA antibody specific for food antigens. Because IgA is at high levels in secretions, it can be found in saliva in addition to serum, and salivary IgA tests are readily available.10,11 

Immunoglobulin-E An immune response to parasites, specifically worms, triggers an IgE response.12 IgE elicits an immune response by binding to Fc receptors on mast cells, eosinophils, and basophils, causing degranulation and cytokine release. In atopic individuals, IgE is also made to allergens. IgE is at low levels in the blood. Measurement of total serum IgE is useful in patients in whom parasitical infection is suspected, but it is not valuable for measuring allergies. Thus the most common method for allergy testing is the skin-prick test.13 In this test, a small amount of the suspected allergen is placed on the skin. Then the skin is pricked so that the allergen goes under the skin’s surface. If the patient is allergic to the allergen, swelling and redness will appear within 15 to 20 minutes. 

Total Antibodies Measuring total antibody in blood involves protein electrophoresis or ELISA and is valuable. However, quantifying the total amount of antibody specific for an antigen is even more desirable. Antibody titers for common antigens, such as those found in vaccines, can be ordered. Each laboratory has its own reference levels for titers because the sensitivity of the test is related to the specificity and affinity of the reagents used. 

Autoantibodies Specific antibodies, rather than total levels, are also measured for circulating autoantibodies. These antibodies can be detected with immunofluorescence, RIA, and ELISA.14 Indirect immunofluorescence is a method often used to investigate autoantibody presence, specifically Antinuclear antibody (ANA). This method involves growing liver cells in a petri dish, exposing the cells to patient serum, then washing any excess antibody away. If the serum contains ANA, these antibodies will stay attached to the nuclear region of the liver cells. The plate is then incubated with an antibody that has a fluorescent tag and is specific to human IgG. When examined under a microscope, a nuclear staining pattern can be observed if the patient has ANA (Fig. 18.3). If the patient does not have ANA, a more diffuse staining pattern occurs. This method is the least sensitive of all the antibody tests, yet it is the gold standard in diagnosing several autoimmune conditions, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).15 Another method of immunofluorescence antibody visualization uses the patient’s tissue as opposed to human cells in a petri dish. This method takes patient tissue that is frozen, and sections are cut on a

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Primary and Adjunctive Diagnostic Procedures ELISA Antibody

Labeling Reagents Enzyme

Binding Site

Substrate Target Analyte (Antigen)

Second Antibody or Target Analyte

Product

Sample

Solid Phase Bind Wash Label Read Fig. 18.2  Enzyme-linked immunosorbent assay (ELISA). A capture antibody specific for an antigen in a sample is attached to the bottom of a plate. The sample (blood, saliva, etc.) is added, and excess sample is washed from the plate. A secondary antibody also specific for the antigen is added to the plate. This secondary antibody is labeled with an enzyme. When the substrate for the enzyme is added to the plate, it elicits a color change. The intensity of the color, as measured by spectrophotometry, indicates the amount of antigen that is present.

Pattern

Associated Antigens

Clinical Associations

Double stranded DNA, histones, DNA/histone complexes, others

SLE, drug-induced lupus, and other conditions

“ENA antigens”: Sm, RNP, SS-A/Ro, SS-B/La Nuclear matrix antigens: (hnRNP), others

Autoimmune rheumatic diseases: SLE, MCTD, Sjögren’s syndrome, and other conditions

Centromere proteins A, B, C located at the kinetochore plates

Scleroderma (CREST syndrome) primary biliary cirrhosis

Fibrillarin, RNA polymerase, NOR-90, Scl-70, Pm/Scl, ribosomal antigens, others

Autoimmune rheumatic diseases: scleroderma, myositis, SLE, and others

Fig. 18.3  Antinuclear antibody (ANA) immunostaining pattern and clinical associations.

cryostat. This tissue is incubated with patient serum, such that autoantibodies in the serum can bind. A fluorescently tagged secondary antibody specific for human immunoglobulin is then used to detect the autoantibodies. Immunofluorescence examination of biopsy specimens of damaged or normal tissue may reveal deposits of immunoglobulins caused by antibodies reacting with an organ or tissue-specific antigens.

This approach is especially important in the diagnosis of antiglomerular basement antibody disease and bullous skin disorders but may show false positives when used for SLE. Current recommendations do not support testing for autoantibodies due to their low specificity, particularly ANA testing, unless clinical suspicion for immune involvement is suspected16 (see Table 18.3 for a listing of common autoantibodies).

CHAPTER 18 

TABLE 18.3  Common Autoantibodies Autoantibody

Clinical Relevance

Antinuclear antibody Smooth-muscle antibody

Systemic rheumatic diseases Nonspecific liver damage; chronic hepatitis Primary biliary cirrhosis Celiac disease; dermatitis; psoriasis Vasculitis Pernicious anemia Idiopathic Addison’s disease Insulin-dependent diabetes mellitus Pemphigus vulgaris; bullous pemphigoid Myasthenia gravis Multiple sclerosis Systemic lupus erythematosus Graves’ disease

Antimitochondrial antibody Endomysial antibody Antineutrophil cytoplasmic antibody Gastric parietal cell antibody Adrenal antibody Pancreatic islet cell antibody Skin antibodies Antiacetylcholine receptor Antimyelin basic protein Double-stranded DNA autoantibody Thyroid stimulating hormone antibody

RIA is a far more sensitive test used for measuring antibodies that are in low concentrations. In RIA, an antibody specific for human antibody is tagged with a radioactive isotope. Because radioactivity is more sensitive than fluorescence, when this antibody is incubated with an autoantibody, the contact detects even low levels of autoantibody. 

Organism-Specific Antibodies Antibody testing can also be used when determining a diagnosis of conditions like infectious mononucleosis due to Epstein–Barr virus (EBV). EBV does not always induce mononucleosis. In fact, only 30% to 40% of those who are infected with EBV will develop mononucleosis.17 With clinical evidence, serological testing can be performed to confirm the diagnosis. Typically, a monospot is performed. A monospot is a form of heterophilic testing, which means that serum is tested against phylogenetically unrelated species’ red blood cells (RBCs), typically horse, ox, or goat. The test is considered positive if the RBCs stick together (agglutination). The antibodies produced early in the infectious process of EBV will cross-react and bind to proteins on the surface of the nonhuman RBCs. If the monospot is positive, a diagnosis can be made. If it is negative, it does not rule out mononucleosis, and further testing can be done at this time. Testing for IgM and IgG antibodies against the EBV capsid antigen is a more specific test for mononucleosis. The presence of IgM indicates an acute infection. IgG antibodies against EBV nuclear antigen appear 6 to 12 weeks after infection and persist for life. Their presence early in the course of illness effectively rules out EBV infection as a diagnosis. In contrast, IgG antibodies against “EBV early antigen” can signify a recent infection. Early antigen antibodies can be further broken down to anti-D and anti-R antibodies. Anti-D antibodies are consistent with early infection and disappear after resolution.18 Measuring antibody titers is a way of assessing vaccination status in individuals who are unsure of their vaccination history or to confirm vaccine protection. Some people are “nonresponders” to vaccines, particularly the hepatitis B vaccine. These individuals do not generate a robust response to a vaccine. Their antibody titers may be below 10 mIU/mL, whereas >10 mIU/mL signifies that an individual is immune. Nonresponders may require further follow-up to determine the etiological mechanism as to why they are nonresponsive to the vaccine.19 Additionally, vaccine titer testing may be used in patients who wish to demonstrate that they have active immunity to

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an infectious agent and do not desire to have additional vaccinations. In cases of pregnancy, vaccine titers may be measured on parents and siblings of the newborn to ensure they are immune to the most common childhood diseases. This strategy capitalizes on the concept of “herd immunity” to ensure newborns’ protection against preventable diseases. 

Urine When an antibody is made, the antibody light chains, κ and λ, are made in excess. These are present as free forms in serum and urine. Although small amounts of light chains are found in everyone, people with renal damage excrete higher levels of light chains in their urine. Free light chains are associated with malignant plasma dyscrasia and other lymphocyte-related immunoproliferative disorders. Intact immunoglobulin can also be found in urine.20 

Cerebrospinal Fluid IgG can be measured in the cerebrospinal fluid (CSF), which is important in the diagnosis of several CNS disease processes, such as multiple sclerosis, neurosyphilis, and subacute sclerosing panencephalitis.21 A sample of CSF and serum is obtained, and the amount of IgG and albumin is recorded in a ratio of IgG:albumin for both samples. Albumin is not synthesized in the brain, so comparing this IgG:albumin ratio of the CSF to the serum sample provides an indirect indication of how much IgG has been synthesized within the brain.1 

MEASUREMENT OF COMPLEMENT AND HIGHSENSITIVITY C-REACTIVE PROTEIN Complement Complement is a series of proteins that result in the destruction of microbes. Assays for complement can either be those that recognize individual complement components (e.g., ELISA for C3 or C4) or functional activity of complement, such as lysis. Measurement of C3 and C4 levels is sufficient, except for rare patients with genetic deficiencies, such as hereditary angioedema. Low levels of complement are more significant than high levels. For example, complement levels may be low in patients with glomerulonephritis or SLE.22,23 However, the complement levels return to normal when patients are in remission. 

High-Sensitivity C-Reactive Protein C-reactive protein (CRP) is involved in the complement pathway (Fig. 18.4). CRP functions by opsonizing bacteria, marking them for destruction by the complement cascade. Because it is readily detectable in the blood, CRP has become an important marker of inflammation. CRP is released early in infection (the first 4–24 hours) during the same window that many other components of inflammation are being activated, such as inflammatory cytokines. CRP levels are an indirect measure of the cytokine interleukin (IL)-6. IL-6 induces production of CRP as part of the initial immune response against an invading pathogen that triggers the rest of the immune response.24 However, because it is far easier to measure than cytokines or other proteins, high levels of CRP are a more consistent marker of a recent infection or heavy immunological involvement, as is the case in several autoimmune diseases.25 Laboratories consistently offer a high-sensitivity test for CRP, called hs-CRP. This test is more sensitive than the original test for CRP, allowing the detection of lower levels of CRP. Consistently high levels of hs-CRP may be diagnostic of chronic inflammation and are values commonly used to determine immune involvement or even cardiovascular disease risk.26 

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Bacteria Polysaccharides ++

Ca

CRP

Binds

Fungi Protozoal Parasite

Lecithin Nucleic Acid

Activate Classical Complement Pathway

Opsonization Lysis Phagocytosis CRP Role in Activation of Complement Fig. 18.4  C-reactive protein (CRP) activates the complement pathway.

TABLE 18.4  Regulatory T Cells Type of Regulatory Cell CD152+)a

Treg cells (CD4+ CD25+ Type I NKT (cells) (NK cells that express a semi-invariant TCR) Tr1 cells (CD4+ CD152+)

Th3 cells (CD4+)

T suppressor cells (CD8+ CD28–) 201029

Cytokines Made

Action

Development of

TGF-β, IL-35 Immunoregulatory Proinflammatory High IL-10 Moderate TGF-β and IFN-γ No IL-2 or IL-4 High TGF-β Low IL-4 and IL-10 No IFN-γ and IL-2 High IL-10

Control overall autoimmune state?

Thymus Thymus

Suppress MS; suppress intestinal inflammation; cytolysis

Periphery systemic differentiate from Th0

Oral tolerance

Periphery differentiate in intestinal mucosa

Suppress DC maturation and function

Periphery

2008.30

Adapted from Venken et al. and Vignali et al. DC, Dendritic cell; IFN, interferon; IL, interleukin; MS, multiple sclerosis; NK, natural killer; NKT, natural killer T cells; TCR, T-cell receptor; TGF, tumor growth factor; Treg, regulatory T cells. anTreg (natural Treg) and iTreg (inducible Treg).

MEASUREMENT OF CELLS

BOX 18.3  Sample Flow Cytometry Dot Plot

Lymphocyte Subpopulations

Flow Cytometry Flow cytometry is a technique for counting cells and other microscopical particles such as cytokines and proteins. Similar to microscopy, flow cytometry allows the identification of cells based on their morphology and cell-surface proteins; however, flow cytometry evaluates cell populations rather than individual cells. Cells are incubated with monoclonal antibodies specific for certain proteins on their surface. Each antibody is tagged with a different color fluorochrome. The cells are then suspended in fluid and passed through the flow cytometer. Light from lasers in the flow cytometer passes through the cells, allowing detectors on the other side to read the light scatter from the cells based on their granularity and size. The detectors also evaluate the colors of the fluorescence associated with each individual cell. The resulting data are plotted using specialized software.

T Cells CD4 T cells make cytokines that direct various arms of the immune system. CD8 T cells kill infected cells. The proteins on the surface of T cells that allow them to be identified are listed in Table 18.4. To qualitatively identify T cells and separate them from other cell types, two proteins are used: CD3 and CD4 or CD8. CD3 is a signaling molecule associated with the T cell receptor and is on all T cells. CD4 and CD8 function to increase the interaction between the T cell and the antigen presenting cell. A sample of how T cells appear on a flow cytometry dot plot is in Box 18.3. In healthy individuals, the CD4/CD8 ratio should be approximately 2:1. This ratio may differ in some ethnic groups.27 CD4/CD8 ratios can be used to evaluate disease progression in patients with human immunodeficiency virus infection. When a clinician approaches a patient with suspected immunodeficiency, he or she may decide to recommend a functional test. Immunodeficiency could be caused by a cell’s inability to proliferate. In this case a lymphocyte proliferation assay or a carboxyfluorescein succinimidyl ester (CFSE) assay would be completed. 

CD4 T Helper Subsets CD4 T cells secrete discrete patterns of cytokines. Each pattern is beneficial for different types of immune responses. A single CD4 T cell specific for a single antigen can secrete any pattern of cytokines but will be skewed toward secreting one pattern or another depending on

CHAPTER 18  the initial trigger. CD4 T helper subsets cannot be identified by surface markers. However, because CD4 T helper subsets secrete different patterns of cytokines, intracellular cytokine staining can discriminate between subsets. The Th0 pattern is secreted by a naïve T cell, that is, one that has not yet seen antigen. It is the cytokine pattern that is designed to simply keep T cells alive. Th0 cells secrete IL-2. The Th1 pattern is secreted by T cells exposed to bacterial or viral antigens. Overactivity of Th1 T cells has been linked to many autoimmune diseases. Th1 T cells secrete interferon-γ, as well as some other cytokines. The Th2 pattern is secreted by T cells exposed to worms and parasites but is also involved in allergy and asthma. Th2 T cells secrete IL-4, IL-5, and IL-13. The Th3 pattern is secreted in response to food. Because the immune response to food should be relatively inert, Th3 cells are considered a type of regulatory T cell (Treg) and are involved in immunological tolerance. Th3 T cells secrete tumor growth factor-β. The Th9 pattern in T cells is closely linked to Th2, and until recently, they were considered to be the same. Th9 T cells produce higher quantities of IL-9 and do not produce IL-4, in direct contradiction to the cytokines produced by Th2 T cells. Th9 T cells have been implicated in the pathophysiology of asthma and other pulmonic conditions. On the other hand, they may play an important role in cancer surveillance and anticancer activities.28 The Th17 pattern is secreted in response to molds and extracellular bacteria. This population of T cells has recently been linked to many autoimmune diseases. Th17 T cells secrete IL-17. 

Regulatory T Cells Tregs play a key role in maintaining tolerance. The loss of Tregs is associated with disease, especially autoimmune disease. Studies of Tregs have been limited largely because of their considerable diversity and lack of unique surface markers; the current state of the science is given in Table 18.4.29,30 Much of the knowledge about Tregs is from mouse models. Human Tregs have been phenotypically identified as CD4+ CD25+, CD4+ CD25high, or CD4+ CD25+ FoxP3+ cells, based on how they stain and present in flow cytometry. CD39 is another protein on the surface of Tregs that may allow reliable identification.31 Although most CD4 T cells express CD127, Tregs display lower surface expression of this marker.32 Tregs behave similarly to other regulatory cells, such as Th3 cells found in the gut and Tr1 cells found in the periphery, but Tregs originate in the thymus and produce different cytokines upon stimulation than these other types of regulatory cells. Activation of Th1, Th2, and Tregs can be measured with the expression of CD69.33 

B Cells B cells are identified by the surface markers CD19 and CD20 (Table 18.5). In addition to being markers for B cells, CD20 is a marker of non-Hodgkin lymphoma and is a current drug target.34 Monoclonal antibodies directed at CD19 are therapeutic targets in rheumatoid arthritis.35 The products of B cells are antibodies and can be measured as described previously. 

Monocytes and Neutrophils Neutrophils and monocytes act early in disease. Tethered to the blood vessel walls, neutrophils are some of the first cells to reach infectious agents. Monocytes can quickly extravasate into tissues, differentiating into macrophages and joining tissue macrophages already present at the site of infection. If monocytes and neutrophils are not functioning properly, severe infections can result. It is rare to find patients with low-functioning monocytes because the consequences can be extreme.

Immune Function Assessment

163

TABLE 18.5  Cell Markers Antigen

Identity/Function

CD3 CD4 CD8 CD16/CD56 CD19/CD20

Present on all T cells Present on T helper cells and some dendritic cells Present on cytotoxic T lymphocytes Combination identifies NK cells B-cell markers

Markers of T cell activation CD25 IL-2 receptor; serves as a marker for Treg cells CD28 Activation marker on CD4 and CD8 T cells CD38 Expressed on T cells after activation; function unknown CD39 Acts on the nucleotide base responsible for enzymatic cleavage of ATP to AMP; marker for Tregs CD45RA Marker of a naïve/resting T cell CD45RO Marker of a recently activated T cell CD69 Early activation marker for T cells, as well as B, NK, monocytes, and neutrophils24 CD71 Early activation marker for T cells CD127 α-Chain of the IL-7 receptor; absence identifies Tregs AMP, Adenosine monophosphate; ATP, adenosine triphosphate; IL, interleukin; NK, natural killer; Treg, regulatory T cells.

When patients have severe staphylococcal or fungal infections, neutrophil numbers should be evaluated, and function should be tested. Neutropenia is more common in neutrophil dysfunction. CD18 is a consistent and reliable marker for neutrophils and can be used as a marker for flow cytometry.36 In healthy individuals, the neutrophil count normally exceeds 1.5 × 109/L. Mild neutropenia is usually asymptomatic, whereas moderate to severe reductions in numbers are associated with a progressive increase in the risk and severity of infections. Episodes of infection are likely to be life threatening when the neutrophil count falls below 0.5 × 109/L. Neutropenia is a frequent side effect of chemotherapy.37 Neutrophil function consists of adhesion, migration, chemotaxis, phagocytosis, and a respiratory burst. Defects in the respiratory burst can cause chronic granulomatosis disease. One simple method to evaluate neutrophil function involves a nitro blue tetrazolium test. In this test, neutrophils ingest and reduce a soluble yellow dye to an intracellular blue crystal. Neutrophils are separated and then stimulated with endotoxin (lipopolysaccharide), and the cells are viewed microscopically. Neutrophils and monocytes can kill microbes with a respiratory burst. Another test of neutrophil function takes advantage of this activity. Neutrophils or monocytes are incubated with live microbes, such as Staphylococcus aureus. After the cells have phagocytosed the organisms, they are washed to remove extracellular organisms. The cells are then lysed, and the lysate is cultured on nutrient agar. Live bacteria will grow on the agar. The number of viable organisms inversely reflects the degree of intracellular killing. 

Natural Killer Cells When cells are infected with a virus or become cancerous, they often express less major histocompatibility complex on their surface. This makes them a target for natural killer (NK) cells. NKs express surface receptors that allow them to recognize the absence of major histocompatibility complex on a target cell and kill it. In addition to this mechanism, NK cells can be identified with CD56.38 Like CD8 activity, NK function can be measured with a 51-chromium release assay (Box 18.3). 

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Primary and Adjunctive Diagnostic Procedures

TABLE 18.6  Cytokine Patterns Immunological Event

Name of Pattern

Cytokines

Inflammation

Proinflammatory

T activation

Th1

IL-1 IL-6 IL-8a TNF-α IFN-γ IL-2 TNF-α GM-CSF IL-4 IL-5 IL-10 IL-13 IL-17 TGF-β IL-4 IL-10 TGF-β IL-10 TGF-β IFN-γ

Th2

T regulation

Th17 Th3

Treg Tr1

GM-CSF, Granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TGF, tumor growth factor; TNF, tumor necrosis factor; Treg, regulatory T cell. aIL-8 is a chemokine.

CYTOKINES Cytokines are immunomodulatory molecules that play an essential role in cell–cell communication and immune reactions. They are produced by most immune cell types, and many physical symptoms of immune dysfunction are triggered by cytokines. Cytokine expression has been studied extensively in autoimmune disorders, chronic inflammation, and other diseases. Cytokine expression is most accurate when measured locally at the tissue site; however, systemic cytokine levels can be detected in serum and saliva. Cytokines may contribute to disease progression and are thus potential targets for therapeutic intervention.39,40 Cytokine levels can be tested with ELISA or cytometric bead array. Because clinical testing for cytokines is relatively new, clinical cytokine testing is not as validated as other forms of testing. Furthermore, cytokine levels are affected by exercise, diet, sleep, age, and gender. Cytokines tend to be secreted in patterns (Table 18.6). Because many natural therapies can modify cytokine expression, skilled clinicians can switch people from one pattern of cytokines to another. 

GENETICS The genetic control of immunity has long been recognized. Many autoimmune diseases map to specific genetic loci. Polymorphisms in the human leukocyte antigen have been linked to insulin-dependent diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. Singlenucleotide polymorphisms (SNPs) in cytokine and cytokine receptor genes are associated with the variability of immune response between individuals to infectious disease.41 Some clinical laboratories now offer testing for SNPs. SNPs are detected using polymerase chain reaction (PCR).42 Gene primer pairs for the candidate gene are used to amplify the DNA sequence of the patient’s gene. The patient’s gene is then sequenced and compared with a standard sequence.

Genetic microarray provides a second test for genetic variability and may allow clinicians to pinpoint genes that are key players in different diseases (Fig. 18.5). In addition to determining patterns of gene expression that contribute to complex disorders, microarray could elucidate gene interactions that lead to clinical symptoms or tell a physician whether a patient is responding to therapy. Microarray involves isolating RNA from tissue, labeling it with fluorescent probe, and then comparing it with a standardized or control tissue by combining the RNA samples and hybridizing them to a chip. The color patterns are read by a computer. The expression of some genes (housekeeping genes) tends to be more stable and can act as a control. There are still several obstacles to overcome with genetic microarray technology, but clinical utility is likely.43 

CLINICAL SYMPTOMS It would be an oversight to exclude clinical symptoms as one of the primary ways that the immune system is evaluated. Clinical symptoms usually occur after an immune response is under way, but they are often the first sign to the patient and physician that something may be amiss. Physicians recognized an immune response long before the first immune cells and proteins were discovered. The classic symptoms of inflammation—calor (heat), dolor (pain), rubor (redness), and tumor (swelling)—were originally described and recorded by Aulus (Aurelius) Cornelius, a Roman physician and medical writer who lived from about 30 BC to 45 AD. These hallmarks of inflammation are caused by many complex interactions between cells and cytokines of the immune and nervous system and allow a clinician to make some assumption about immune processes without even drawing blood. For example, calor (heat) refers to fever. If a patient has a fever, a physician may assume that IL-1β is elevated. Table 18.7 illustrates which immune processes underlie the hallmarks of inflammation.

Sickness Behavior Proinflammatory cytokines act in the brain to induce nonspecific symptoms of infection. In addition to triggering fever, cytokines elicit profound psychological and behavioral changes. Sick individuals experience several symptoms, including malaise, fatigue, weakness, an inability to concentrate, and listlessness. They become sleepy (hypersomnia) and experience depressed activity and a desire to be isolated. These infection-induced changes are referred to as ‘‘sickness behavior.”44 Sickness behaviors have a variety of advantages to both the sick individual and the population at large. Malaise, fatigue, and listlessness cause a person to rest and thus conserve energy. Rest further aids the body by decreasing heat loss, whereas shivering increases heat production. Social isolation may help prevent the spread of the infection to others.45 Most sickness behaviors are caused by cytokines, and they may help an observant clinician make a diagnosis. For example, fatigue and malaise are most commonly triggered by IL-1β. Interestingly, in some people, tumor necrosis factor-α and IL-6 may cause anger or hostility, and this emotional response leads to the social isolation.46 

SUMMARY Choosing appropriate immunological tests requires physiological, economic, and ethical considerations. To choose the right test for the patient, the reliability of the tests, as well as their specificity and sensitivity, must be considered. Assessing the immune system is further complicated by its sensitivity to the environment. Thus running tests in duplicate or triplicate may be necessary to validate results.

CHAPTER 18 

Immune Function Assessment

Fig. 18.5  DNA microarray. RNA is prepared from a collection of cells, normal and/or diseased. The RNA is translated into cDNA in vitro. The cDNA from each cell type is labeled with a different color of fluorescent dye. These cDNAs are then added to a chip or bead that has been previously hybridized with DNA probes. A computer analyzes the color of the DNA spots on the chip or bead. Relative difference in color indicates difference in gene expression between the two cell types.

TABLE 18.7  Hallmarks of Inflammation

REFERENCES

Latin

English

Cytokines and Cells Involved

Calor

Heat

See www.expertconsult.com for a complete list of references.

Dolor

Pain

Rubor

Redness

Tumor

Swelling

IL-1β, IL-6 act at the hippocampus, causing the body to increase blood flow, resulting in heat. TNF-α and IL-1β lead to localized edema that nerve endings sense as pain. TNF-α and IL-1β cause vasodilation and increased blood flow. TNF-α and IL-1β cause increased permeability of the capillaries.

IL, Interleukin; TNF, tumor necrosis factor.

165

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22. Kao AH, et al. Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus. Arthritis Rheum. 2010;62:837–844. 23. Ponticelli C, Coppo R, Salvadori M. Glomerular diseases and transplantation: similarities in pathogenetic mechanisms and treatment options. Nephrol Dial Transplant.. 2011;26:35–41. 24. Nakken B, et al. Biomarkers for rheumatoid arthritis: from molecular processes to diagnostic applications-current concepts and future perspectives. Immunol Lett. 2017;189:13–18. 25. Genest J. C-reactive protein: risk factor, biomarker and/or therapeutic target? Can J Cardiol. 2010;26(suppl A):41A–44A. 26. Plazak W, et al. Influence of chronic inflammation and autoimmunity on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients. Inflamm Res. 2011;60:973. 27. Jiang W, et al. Normal values for CD4 and CD8 lymphocyte subsets in healthy Chinese adults from Shanghai. Clin Diagn Lab Immunol. 2004;11:811–813. 28. Zhao P, Xiao X, Ghobrial RM, Li XC. IL-9 and Th9 cells: progress and challenges. Int Immunol. 2013;25:547–551. 29. Venken K, Hellings N, Liblau R, Stinissen P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med. 2010;16:58–68. 30. Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523. 31. Mandapathil M, Lang S, Gorelik E, Whiteside TL. Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J Immunol Methods. 2009;346:55–63. 32. Hartigan-O’Connor DJ, Poon C, Sinclair E, McCune JM. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods. 2007;319:41–52. 33. Ziegler SF, Ramsdell F, Alderson MR. The activation antigen CD69. Stem Cells Dayt Ohio. 1994;12:456–465. 34. van Meerten T, Hagenbeek A. CD20-targeted therapy: the next generation of antibodies. Semin Hematol. 2010;47:199–210. 35. Tedder TF. CD19: a promising B cell target for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5:572–577. 36. Stroncek D. Neutrophil alloantigens. Transfus Med Rev. 2002;16:67–75. 37. Lyman GH. A comparison of international guidelines for the prevention of chemotherapy-induced neutropenia. Curr Opin Hematol. 2011;18:1–10. 38. Timmons BW, Cieslak T. Human natural killer cell subsets and acute exercise: a brief review. Exerc Immunol Rev. 2008;14:8–23. 39. Fox PC, Brennan M, Di Sun P. Cytokine expression in human labial minor salivary gland epithelial cells in health and disease. Arch Oral Biol. 1999;44(suppl 1):S49–S52. 40. Suh KI, Kim YK, Kho HS. Salivary levels of IL-1beta, IL-6, IL-8, and TNF-alpha in patients with burning mouth syndrome. Arch Oral Biol. 2009;54:797–802. 41. Pankratz VS, Vierkant RA, O’Byrne MM, Ovsyannikova IG, Poland GA. Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment. BMC Immunol. 2010;11:48. 42. Germer S, Holland MJ, Higuchi R. High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res. 2000;10:258–266. 43. Kim K, Zakharkin SO, Allison DB. Expectations, validity, and reality in gene expression profiling. J Clin Epidemiol. 2010;63:950–959. 44. Kent S, Bluthé RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol Sci. 1992;13:24–28. 45. Kelley KW, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003;17(suppl 1):S112–S118. 46. Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–563.

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19 Intestinal Permeability Corene Humphreys, ND, BHSc, Dip Med Herb, Dip Hom, QTA

OUTLINE Introduction, 166 Components of the Intestinal Barrier, 166 The Microbiological Barrier, 166 The Physical Barrier, 167 The Biochemical Barrier, 169 The Immunological Barrier, 169 Luminal Transport Across the Intestinal Epithelium, 170 Assessing Intestinal Barrier Function, 170 Active Assessment of Barrier Function, 170 Passive Assessment of Barrier Function, 171 Factors Affecting Intestinal Permeability, 172 Enteric Infections, 172

INTRODUCTION The intestinal epithelial barrier (IEB) is a dynamic, multicomponent barrier tasked with the important role of keeping out harmful molecules from the external environment while simultaneously allowing the absorption of nutrients and water vital for host survival. Over the past decade, substantial scientific and clinical research has been undertaken in this field of physiology. Alterations in IEB function have now been implicated in the pathogenesis of a number of chronic inflammatory diseases, including intestinal diseases, cardiometabolic disorders, autoimmune diseases, lung disease, neurological conditions, and systemic infectious diseases. This chapter outlines the core components and pathophysiological roles of the IEB and how they relate to specific disease states. It also outlines key diagnostic tests to identify changes in gut permeability, along with evidence-based therapies to restore intestinal barrier homeostasis. 

COMPONENTS OF THE INTESTINAL BARRIER Spanning approximately 300 to 400 m2, the gastrointestinal barrier represents the largest surface area in the body that separates the external environment from the internal milieu.1,2 The primary roles of the IEB are to protect the host from luminal pathogenic bacteria, intraluminal toxins, and antigens while simultaneously allowing for the passage of dietary nutrients, electrolytes, and water.1,3–5 Structures of the IEB comprise four diverse components: microbiological, physical, chemical, and immunological barriers (Fig. 19.1).1

The Microbiological Barrier The gut microbiota is now recognized as an integral component of the intestinal epithelial barrier for a number of reasons: (1) it promotes resistance to the colonization of pathogenic organisms by competing

166

High-Fat Diet, 172 Gluten/Gliadin, 172 Food Allergies and Intolerance, 172 Nonsteroidal Anti-Inflammatory Drugs and Proton-Pump Inhibitors, 173 Exposure to Xenobiotic Pollutants, 173 Gastrointestinal and Systemic Diseases Associated with Altered Intestinal Barrier Function, 174 Therapeutic Considerations, 174 Nutraceutical Therapies, 174 Pharmaceutical Medications for Altered Intestinal Permeability, 175

for attachment sites, (2) it provides nutrients, and (3) it releases antimicrobial substances. The microbiota is also involved in the digestion and absorption of luminal nutrients, which in turn supply energy to intestinal epithelial cells.6–9 Over 90% of the human microbiota is derived from seven phyla: Firmicutes (gram positive), Bacteroides (gram negative), Proteobacteria (gram negative), Fusobacteria (gram negative), Verrucomicobia (gram negative), Cyanobacteria (gram negative), and Actinobacteria (gram positive), with Firmicutes and Bacteroides as the dominant species.10–12 A dysbiosis can be defined as a reduction in microbial diversity and a combination of the loss of beneficial bacteria such as Bacteroides strains and butyrate-producing bacteria such as Firmicutes10 and a rise in pathobionts12 (symbiotic bacteria that become pathogenic under certain conditions), including Proteobacteria, which encompasses gram-negative Escherichia coli.13 Lipopolysaccharides (LPSs) constitute the major lipidic components of the outer wall of gram-negative bacteria. They are vital for the structure and functional integrity of these bacteria, providing a barrier that protects against penetration of bile salts and other antimicrobial agents while allowing the passage of small hydrophobic compounds. For the host, however, persistent migration of LPSs into the circulatory system can have deleterious consequences.12 LPSs have also been identified in the scientific literature as “endotoxins.”13 Endotoxins bind to receptors, initiating an adaptive immune response and a signaling cascade, leading to activation of proinflammatory genes.14 Impaired digestive function along with gut-derived microbial toxins trigger both the onset and maintenance of chronic low-grade inflammation.15 This, in turn, increases intestinal permeability, allowing the translocation of microbiome-derived LPSs into the bloodstream, resulting in a two- to threefold increase in serum LPS concentration, which can reach a threshold termed metabolic endotoxemia (ME). ME may

CHAPTER 19 

Intestinal Permeability

167

Fig. 19.1  Components of the intestinal barrier. (From Ji J, Qu H, Shu D. Crosstalk between bioactive peptide and intestinal barrier in gut homeostasis. Curr. Protein Peptide Sci. 2015;16[7]:604–612.)

trigger toll-like receptor-4 (TLR-4)–mediated inflammatory activation, eliciting chronic low-grade proinflammatory and prooxidative stress. Endotoxemia has been implicated in a number of inflammatory diseases, including sepsis, septic shock, diabetes, and, more recently, obesity-related metabolic disorders. Gut microbiota constitutes the major source of LPSs, and the main portal of entry into the systemic circulation is via direct diffusion through increased intestinal permeability, or from the absorption and incorporation of LPSs into chylomicrons after a lipid-rich meal.12,16 Research shows that impaired intestinal barrier function is often associated with alterations in the gut microbiome. When this occurs, instead of maintaining the homeostasis of the immune system, the microbiota can initiate and perpetuate inflammatory responses, thereby triggering or exacerbating intestinal and systemic diseases such as inflammatory bowel disease (IBD) and metabolic syndrome.11,13,17,18 

The Physical Barrier The physical barrier comprises the mucus layer, intestinal epithelial cells, and intercellular junctional complexes.6 The chief role of this component of the IEB is to prevent bacterial adhesion (mucus layer) and regulate transcellular and paracellular diffusion of molecules into the systemic circulation (epithelial cells and tight junctions).19

The Mucosal Layer Immediately below the microbiota and overlying the epithelium is the mucus layer, which functions as both a physical barrier and a biochemical barrier.5 As the first physical barrier, the mucus layer limits the direct interactions of the intestinal epithelium with microbes, antigens, and toxins while simultaneously allowing nutrient absorption.17,18,20 The mucosal layer also acts as a lubricant for intestinal motility.21 Specialized enterocytes called goblet cells secrete mucus, which is composed of proteins, carbohydrates, lipids, and water.22 A core

component of mucus is large glycoproteins, which belong in the family of secretory-gel–forming mucins. In both the small and large intestine, MUC2 is the primary secretory mucin produced and secreted by goblet cells and forms the main structural unit of the mucus layer.5,22 As well as acting as the first line of defense against physical and chemical injury from luminal microbial and antigenic contents, secreted mucins serve as a food source for microbes and also provide binding sites for bacteria.12,19,22,23 At the same time, microbiota and their microbial products are able to modulate mucin synthesis and release through a “crosstalk” feedback mechanism. Thus a symbiotic relationship exists whereby microbiota and mucins work collectively to prevent the invasion of enteric pathogens.22 

Intestinal Epithelial Cells Below the mucus layer is the intestinal epithelium, which is organized into a monolayer of invaginations called crypts and villi (finger-like projections) in the small intestine. The bottom of the crypt is composed of stem cells, which differentiate into mature cell lineages as they migrate up toward the villus.22,24,25 To date, at least seven different cell lineages have been identified: enterocytes, goblet cells, Paneth cells, microfold cells (M cells), endocrine cells, cup cells, and tuft cells.6,21 The exact roles of cup and tuft cells have not been fully elucidated.6 The key physiological roles of the main intestinal epithelial cells are outlined as follows: Enterocytes comprise approximately 90% of IECs and play an important role in the absorption of nutrients while also serving as a barrier to prevent the translocation of luminal contents into host tissues.6,19 Goblet cells secrete mucin and other mucus constituents that form a net-like structure to protect microorganisms from reaching the epithelial surface.26 They have also been shown to secrete antimicrobial peptides (AMPs) known as trefoil factors, which are involved in intestinal defense and mucosal repair.1

168

SECTION 2 

A

Primary and Adjunctive Diagnostic Procedures

B

C Fig. 19.2  Transmembrane and Intracellular Mechanisms of Paracellular Permeability. (From Barreau F, Hugot JP. Intestinal barrier dysfunction triggered by invasive bacteria. Curr. Opin. Microbiol. 2014;17:91-98.)

Paneth cells are composed of large numbers of secretory granules filled with AMPs, and as such, they support and mediate the biochemical barrier function.5 Antimicrobial substances secreted by Paneth cells include defensins, lysozyme, and regenerating islet-derived protein 3-gamma (RegIIIγ) proteins, all of which help protect against infection from bacteria, fungi, yeasts, and viruses.1,26,27 Microfold (M) cells represent the antigenic component of the intestinal epithelial barrier. Located above the Peyer’s patches and intestinal lymphoid follicles, M cells are involved in the process of sampling antigenic material, including food antigens, pathogenic bacteria, and their bacterial components, from the lumen and transcytosing to the underlying immune system.28–31 Commensal bacteria can also be internalized and exported to the gut-associated lymphoid tissue (GALT) via this pathway.31,32 Enteroendocrine cells are sensory intestinal epithelial cells that detect and respond to luminal nutrient content by secreting peptide hormones to regulate digestive enzyme secretion, intestinal pH, gastric emptying, satiety, electrolytes, and motility.33–36 Hormonal mediators secreted by enteroendocrine cells include serotonin, motilin, glucagon-like peptide NPY, and substance P.34 Enteroendocrine cells comprise less than 1% of the overall intestinal epithelial population, of which serotonin-secreting enterochromaffin cells are the most abundant subtype.33 Despite their small representation, because they are dispersed throughout the gastrointestinal tract, these cells collectively constitute the largest endocrine system in humans.35 

Intercellular Junctional Complexes Intestinal epithelial cells are tightly bound to one another by at least four intercellular junctional complexes, which are vital for the integrity of the epithelial barrier.37,38 From apical to basal, the intercellular junctions are composed of tight junctions (zonula occludins), adherens junctions (zonula adherens), desmosomes, and gap junctions (Fig. 19.2).9,19,39,40 

Tight Junctions (Zonula Occludins) Tight junctions represent the most apical (the side toward the lumen) structure of the intercellular junctional complex and are composed of at least 50 different transmembrane proteins.9,18,21,37,38 Numerous in vitro and animal studies have identified tight junction disruption as the leading cause of altered intestinal barrier function.38,39 The primary function of tight junctions is to provide a physical barrier that selectively allows for the passage of water, ions, and small solutes in the space between neighboring cells while limiting access to pathogens, toxins, and xenobiotics.18,24,41–43 The four integral transmembrane proteins that make up the tight-junction complex are occludin, the claudin family, tricellulin, and the junctional adhesion molecule (JAM).39,40 Occludin, tricellulin, and JAM play a regulatory role in tight-junction structure and permeability,3,20,27,34,44,45 whereas the claudin family is primarily responsible for intestinal barrier function.26,27,46 Claudins can be differentiated into two main types: barrier enhancing (those that decrease paracellular permeability) and pore forming (claudins that increase paracellular permeability).20,26,31,46 The specific claudins identified with the sealing function that decreases paracellular permeability include claudin-1, -3, -4, -5, -8, -9, -11, -14, and -19.18,31,47 Claudins linked to pore formation and enhanced permeability include claudin 2, -7, -10, -12, -15, and -23.18,48 Zonula occludins proteins (ZO-1, ZO-2, and ZO-3) are intracellular scaffold proteins that anchor the transmembrane proteins to the cytoskeleton of the cell.18,27,42,46 Zonulin is recognized as the only physiological regulator of intracellular tight junctions and also plays an important role in the balance between tolerance and immunity.49,50 Gluten and bacteria (commensals and pathogenic) in the intestinal mucosa have been identified as stimuli that can trigger the release of zonulin.49,51 Together, transmembrane and zonulin proteins form a connective network around intestinal epithelial cells via their interaction with the perijunctional actomyosin ring (a dense ring of filamentous actin and myosin that encircles the cell at the region of the adherens junctions and tight junctions).9,17,18,21,24 Tight-junction functionality is also

CHAPTER 19  regulated in part by myosin light chain (MLC) phosphorylation with the enzyme MLC kinase, which causes actin to contract and open the junctional gap. This results in increased permeability to electrolytes and other small organic molecules.11,18,20,43 Historically, the tight-junction complex was thought to be a simple, static paracellular seal. New evidence shows that tight junctions are dynamically and selectively permeable and are able to regulate paracellular flux in both a size- and charge-selective manner.43,47,51,52 Physiological and pathological factors known to influence tight-junction permeability include dietary peptides, probiotics, enteric pathogens, mucosal immune activation, cytokines, proteases, cellular stress, growth factors, and enteric nervous system signaling.25,50,52 

Adherens Junctions (Zonula Adherens), Desmosomes, and Gap Junctions Located immediately below the tight junctions are the adherens junctions, followed by desmosomes and then gap junctions.24 Adherens junctions and desmosomes form strong adhesive bonds between IECs to hold cells together and protect against mechanical disruption of the epithelial sheet. They are also involved in cell-to-cell communication and are home to proteins that direct epithelial polarization.12,18,20,24,39,45 Gap junctions are also involved in intracellular communication and help facilitate the exchange of small molecules between intestinal epithelial cells.9,48,53 Unlike tight junctions, however, these proteins do not regulate paracellular permeability.12,18,20,24,39,45 

The Biochemical Barrier Embedded in the mucus layer and far into the gastrointestinal lumen resides the biochemical barrier. The main role of the biochemical barrier is to reduce the load of colonized bacteria and help prevent luminal antigens from having direct contact with host cells.6 Components that make up the chemical barrier include digestive secretions, AMPs, cytokines, and other inflammatory mediators such as proteases.26

Intestinal Permeability

169

TABLE 19.1  Effects of Cytokines and

Growth Factors on Intestinal Epithelial Barrier Function Cytokine/Growth Factor IFN-γ TNF-α IL-1β IL-4 IL-6 IL-10 IL-13 IL-17 TGF-α TGF-β EGF

Effects on Intestinal Barrier Function ↑ paracellular permeability ↑ paracellular and transcellular permeability ↑ paracellular and transcellular permeability ↑ paracellular permeability ↑ paracellular permeability to cations Restores intestinal barrier defects (neutralizes IFN-γ) ↑ paracellular permeability ↓ paracellular permeability Protects against barrier defects (neutralizes free radicals) ↓ paracellular permeability Protects against barrier defects (neutralizes free radicals)

EGF, Epidermal growth factor; IFN-γ, interferon-gamma; IL, interleukin; TGF-α, transforming growth factor-alpha; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha.

depending on the particular cytokine involved (Table 19.1).3,45 The secretion of proinflammatory cytokines in response to dysbiotic microbiota and other noxious stimuli has been shown to impair gut barrier function and induce the reorganization of a number of tight-junction– associated proteins.7,34,42 

Proteases

The first line of biochemical defense resides within the lumen, where gastric acid, pancreatic juice, and bile participate in the integrity of the intestinal epithelial barrier by altering the pH, thereby creating a bactericidal environment for pathogenic organisms.19,21 In addition to their antimicrobial role, digestive enzymes degrade dietary proteins, thereby preventing larger immunogenic peptides from reaching the small intestine.30 

Proteases can be present on both the apical and basolateral sides of the intestinal wall. In the gut lumen, they are either produced endogenously (e.g., pancreatic proteases) or from bacteria and food particles. In the lamina propria, proteases are released into the mucosa by macrophages, neutrophils, and mast cells to regulate inflammation.2 Proteases play a dual role, acting as both degrading enzymes and signaling molecules. In the gastrointestinal mucosa, they are involved in the degradation of the extracellular matrix, mucosal proteins, and bacteria. As signaling molecules, their proteolytic action is capable of altering the structure and function of tight junctions, thereby increasing intestinal permeability.2,26 

Antimicrobial Peptides

The Immunological Barrier

AMPs are secreted by virtually all epithelial cells in the intestine as well as immune cells.9,18 The chief role of AMPs is to protect the intestinal epithelial barrier against invading pathogens and control the colonization of commensal organisms.6,12,32,54 AMPs are active against a variety of organisms, including gram-positive and gram-negative bacteria, parasites, protozoa, fungi, and enveloped viruses.18,54 AMPs destroy bacteria either by enzymatic attack or via nonenzymatic mechanisms that interfere with bacterial membranes via electrostatic interactions.32 To date, several types of AMPs have been identified, including α-defensins and β-defensins, C-type lectins, cathelicidin, lysozyme, and intestinal alkaline phosphatase.6 In addition to their role as antimicrobial agents, AMPs also represent a link between the innate and adaptive immune systems.5,9 

Residing immediately below the epithelial layer is the lamina propria, which is home to the intestinal immune system.13 The innate and adaptive immune systems contribute to the immunological barrier, and together, they form the gut-associated lymphoid tissue (GALT), which contains up to 70% of the entire body’s immune cells.19,21 Within the GALT are organized lymphoid follicles, including Peyer’s patches, which are primarily located in the distal ileum, and isolated lymph follicles that are mainly found in the colon.28 The immune cells that make up the innate and adaptive immunity of the gastrointestinal tract include dendritic cells, monocyte/macrophages, neutrophils, mast cells, B cells, and T cells.28 Collectively, these cells are responsible for antigen sampling and immunological responses to pathogenic microorganisms as well as immune tolerance to commensal flora.19,21,50 Secretory immunoglobulin A (sIgA) is the first line of adaptive immune defense and constitutes the major immunoglobulin class in the gastrointestinal tract.1,18 Immunoglobulin A (IgA) is secreted by

Digestive Secretions

Cytokines Intestinal epithelial barrier function is also regulated by cytokines, which can have barrier-disrupting or barrier-enhancing effects,

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plasma cells (effector B cells) in the lamina propria and is then transcytosed through the intestinal epithelium (with the aid of the polymeric immunoglobulin receptor) and secreted into the lumen as sIgA antibodies.1,6,13,28 Once in the lumen, sIgA binds to bacteria and viruses, thereby preventing them from attaching to and colonizing epithelial surfaces.18,26 Another way in which sIgA exerts antimicrobial effects is by entrapment of bacteria in the mucus layer, reducing bacterial virulence factors and phagocytosis of intracellular pathogens as it migrates through the epithelium.13,55 

LUMINAL TRANSPORT ACROSS THE INTESTINAL EPITHELIUM Epithelial cells allow for selective permeability by three distinct pathways: the transcellular route, the paracellular route, and the more recently identified unrestricted pathway.20,39,45 The transcellular transport pathway facilitates the passage of larger molecules (molecular weight [MW]: >600 Da) through the intestinal epithelial cells.25 Nutrients such as sugars, amino acids, peptides, fatty acids, and vitamins and minerals utilize this pathway.40,45 Food antigens, bacteria, and bacterial products, including LPSs, primarily use the transcellular route via M cells and other enterocytes such as goblet cells.12,25,40 These antigens are normally degraded by lysozymes within the intestinal epithelium and enter the lamina propria as small, nonimmunogenic peptides.17 To date, a number of different transcellular pathways have been described for different luminal compounds based on their size, hydrophobicity, and other chemical traits12,25,45,56: Transcellular uptake—this route is through the plasma membrane of epithelial cells. Small hydrophilic and lipophilic compounds and ions utilize this pathway. Active transport—nutrients such as sugars, amino acids, and vitamins and minerals migrate through the epithelial barrier using transporters, which requires energy (hence the name “active” transport). Endocytosis—larger molecules, including proteins, larger peptides, bacteria, and bacterial products, are endocytosed into vesicles and move through the intestinal epithelium via transcytosis and posterior exocytosis. The paracellular pathway allows for the transport of ions (mostly cations), water, and other inert solutes of low molecular weight (906 nmol/L 0.3 mg/dL 30 mcg/108 WBCs 0.3–2.0 mg/h in control 24–49 mg/h after 500 mg

Urinary N-methylnicotinamide 2-pyridone 5-carboxamide (2-PYR) RBC NAD/NADP

>1.6 mg/g creatinine

Pantothenic acid

Urinary pantothenic acid

>1 mg/day

Pyridoxine

Serum level Plasma pyridoxal 5-phosphate Urinary 4-PA Serum homocysteine

5.0–50.0 ug/L >30 nmol/L

Riboflavin

EGRAC

150 pg/mL 1.6 mg/g creatinine >1.3

>3.0 mol/d 20 >30 >20

Vitamin D

25 (OH) vitamin D

40–80 ng/mL

Vitamin E

Plasma α-tocopherol α-tocopherol:cholestrol

>16.2 μmol/L >5.2 μmol/L

Vitamin K

% serum uncarboxylated osteocalcin

T, –13915T>G, –14010G>C, –13937G>A, –13907G>C, and –13913T>C. Respective to these SNPs, the variant alleles associated with lactase persistence are T, T, C, G, G, and T.3,22,25,27–30 Although the presence of any these SNPs suggests lactase persistence, their absence does not equate to lactase nonpersistence because there appear to be other SNPs that have not yet been determined.31 

ACQUIRED (SECONDARY) LACTASE DEFICIENCY Because LPH is located in the brush border (microvilli) of gut mucosal cells, LPH deficiency may be secondary to diseases that damage these cells. Lactose intolerance has been observed as a secondary feature in celiac disease,32 tropical sprue, acute gastroenteritis, chemotherapy-induced mucositis,33 cystic fibrosis, alcoholism,34 pelvic radiation therapy,35 and Crohn’s disease.36 In secondary lactase deficiency, treating the underlying condition and resultant restoration of mucosal integrity often restores lactase activity.37 

CONGENITAL LACTASE DEFICIENCY Congenital lactase deficiency is a rare inborn error of metabolism characterized by very low or absent lactase activity in the intestinal microvilli at birth. Unlike lactase nonpersistence mutations, which affect upstream enhancer regions of LCT, mutations in the LCT gene itself appear to be responsible for congenital lactase deficiency.38 Clinical symptoms include severe diarrhea, dehydration, and malnutrition and

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BOX 21.1  Symptoms of Lactose Intolerance

BOX 21.2  Sources of Lactose

Indigestion Bloating Flatulence Nausea Diarrhea Failure to thrive Abdominal cramps

Obvious Sources Milk (whole, skim, dry powdered, evaporated) Cheeses Butter, many margarines Goat’s milk Half-and-half cream Ice cream and many sherbets Yogurt 

often appear during the first week with the consumption of lactose. Separately, preterm infants may exhibit symptoms of lactase deficiency if born before 34 weeks’ gestation, a condition called developmental lactase deficiency.39 As expected, preterm infants can gain function of the lactase enzyme with time. 

LACTOSE INTOLERANCE VERSUS DAIRY ALLERGY Lactose intolerance and dairy allergy are separate pathologies. Lactose intolerance results from the maldigestion of dairy carbohydrate (lactose), whereas dairy allergy is an immune response to dairy proteins (e.g., casein, lactalbumin, whey). Dairy allergy may involve reactions (e.g., systemic anaphylaxis) that affect the gastrointestinal tract, skin, respiratory tract, or multiple systems. These immediate reactions are often mediated by immunoglobulin-E (IgE) and can cause severe morbidity and even death; however, in such cases, dietary elimination of dairy products is associated with good prognosis.40 The prevalence of IgE-mediated allergic reaction to dairy protein in the general population is estimated at 1% to 3%, being highest in infants and lowest in adults. However, the prevalence of IgG-mediated allergic reactions may be higher. 

DIAGNOSIS OF LACTOSE INTOLERANCE Clinical suspicion of lactose intolerance should be raised when foods containing milk or milk products produce symptoms of gas, bloating, cramping, or diarrhea (Box 21.1). A short course of dietary manipulation, with careful removal of milk-containing products, can strengthen the case for lactose intolerance as a diagnosis. Stool acidity testing, oral lactose tolerance testing, breath tests for hydrogen and methane, and/ or genomic evaluation for LCT haplotypes should be used to confirm the diagnosis. Because the presence of lactase deficiency does not always result in lactose intolerance, genomic testing should never be used as a sole determinant in diagnosis. Breath testing provides the most reliable, noninvasive means of determining lactose malabsorption but must be used in the context of symptomology to make the diagnosis of lactose intolerance. In contrast, a positive breath test coupled with the absence of LCT haplotyping indicating primary lactase deficiency suggests a secondary causation, the diagnosis of which should be pursued. There have been conflicting results regarding the presence of lactose intolerance in patients with irritable bowel syndrome (IBS). By definition, the diagnosis of IBS is a functional diagnosis that is made when all organic causes of symptoms have been ruled out. However, studies have shown that patients with IBS have a high rate of lactose intolerance, with the resolution of IBS symptoms upon lactose limitation or removal.41–43 Rana et al.44 found that patients with diarrhea-predominant IBS had a higher incidence of lactose intolerance (82%) than patients who had either spastic-type IBS or features of both IBS types. For this reason, lactose intolerance should always be investigated in cases of IBS, a condition that affects up to 20% of Americans.45

Hidden Sources Artificial sweeteners containing lactose Breads, biscuits and crackers, doughnuts made with milk Breading on fried foods Breakfast and baby cereals containing milk solids Buttered or creamed foods (soups and vegetables) Cake and pudding mixes, many frostings Candies with milk chocolate Cookies made with milk Hot dogs, luncheon meats, sausage, hash, processed and canned meats Mayonnaise and salad dressings made with milk Nondairy creamers (except for Coffee Rich)

A number of studies have suggested that transient lactose intolerance is also associated with infantile colic.46,47 For susceptible children with lactose maldigestion, only 12 g of lactose (∼1 cup of milk) daily has been shown to be associated with increased abdominal pain.48

Nutritional History A detailed history of the patient’s average consumption of lactose-containing food should be obtained. Often, patients do not consider yogurt, ice cream, chocolate milk, and milk ingested with cereal as important sources of lactose. They also may not be aware that lactose is added to many nondairy products to provide texture, flavor, and browning and to absorb flavors, aromas, and food colors (Box 21.2). In addition, because of its excellent binding ability, lactose is contained in many drugs and over-the-counter products (Box 21.3). Identifying all sources of lactose is necessary to (1) identify the potential relationship between gastrointestinal symptoms and lactose consumption and (2) develop an effective lactose-free diet, if necessary. 

Empirical Testing (Trial Elimination of Milk Products From the Diet) If the patient experiences symptoms after consuming food products containing lactose, the temporary exclusion of all lactose-containing products from the diet as a preliminary diagnostic procedure may be helpful. However, the diagnosis of lactose intolerance should not be based solely on the elimination of milk products. This subjective test may be misleading if hidden sources of lactose (see Box 21.3) are not removed or if unrelated symptoms coincidently abate during this period.49 

Stool Testing The fermentation of undigested disaccharides of any kind within the colon results in the overproduction of fatty acids by colonic bacteria, which lowers the pH of the stool. Normal stool pH is between 6.0 and 7.0 in young children and adults. Although infants may normally have a lower pH due to a high-lactose diet, a pH of less than 5.3 suggests maldigestion. Although pH testing can be used to raise the clinical suspicion of malabsorption, further workup is warranted to make a diagnosis of lactose intolerance. 

CHAPTER 21 

Lactose Intolerance Testing

185

BOX 21.3  Prescription and Over-the-

carbon molecule (13C) in the lactose structure showed poor correlation with lactose intolerance, as evidenced by poor 13CO2 output by the lungs.53

Prescription Drugs Ativan Bumex Calan Coumadin tablets Erythromycin Glucotrol Lasix Lotronex Mevacor Premarin Prilosec Propecia Reglan Synthroid Vasotec Xanax 

Procedure

Counter Drugs Containing Lactose

Over-the-Counter Drugs Actifed tablets Allbee C-800 Plus iron tablets Benadryl tablets Chlor-Trimeton Allergy tablets Ferro-Sequels Imodium A-D caplets Marezine tablets Pepcid AC chewable Slow FE iron tablets Sudafed Plus tablets Unifed Chewable tablets

Breath Testing Breath testing is the method of choice for diagnosing lactose maldigestion.50 It is sensitive and specific,51 simple to perform, noninvasive, and inexpensive.49 Breath testing is based on the ability of intestinal microbes to ferment carbohydrates, in this case lactose, producing hydrogen or methane in the process. A fraction of these gases naturally diffuses from the bowel to the circulation and is eliminated via the lungs. Because there is no other metabolic production of hydrogen and methane, pulmonary excretion of these gases may be used as an indirect measure of lactose maldigestion, indicating lactase deficiency.52 The benefits of breath testing are as follows: • Its results correlate strongly with the symptoms of lactose intolerance.53 • It can be done at home by the patient or in the physician’s office.54 • The lower challenge dose of lactose causes significantly fewer side effects than the large doses used in blood and urine galactose tests.55 • The breath hydrogen/methane test is the standard in pediatric cases in which other tests would be difficult to perform.56–58 Historically, breath testing measured hydrogen only. However, Tormo et al.59 showed that methane is produced instead of hydrogen in some patients with lactose malabsorption. They concluded that measuring both gases was necessary for accurate diagnosis of lactose maldigestion. Other researchers suggested that although methane was produced predominantly in some cases, hydrogen production correlated more strongly with symptoms; therefore hydrogen testing alone might be sufficient for the diagnosis of lactose intolerance.60,61 Breath testing using a radiolabeled

After an overnight fast, a baseline breath sample is collected 30 minutes after rising. The patient then ingests a challenge dose of lactose (up to a maximum of 25 grams), and breath samples are collected 1, 2, and 3 hours after ingestion of the challenge dose.62,63 

Interpretation If lactose maldigestion is present, breath levels of hydrogen or methane will rise within 1 to 2 hours after ingesting the lactose challenge. As little as 2 g of carbohydrate reaching the colon produces a detectable increase in breath hydrogen.64 

Hydrogen and Methane Responses The normal breath hydrogen level in a healthy, fasting patient is less than 10 ppm. Patients with lactose malabsorption show an increase in breath hydrogen concentration of 20 ppm or more during the test.65,66 The normal breath methane level in a fasting patient is 0 to 7 ppm. An increase of at least 12 ppm of methane alone during the test is considered positive for lactose malabsorption, regardless of the hydrogen response.67–69 If both breath hydrogen and methane rise after a lactose challenge, the two responses are added to estimate the degree of malabsorption. The increases in breath hydrogen and methane levels together must be 20 ppm or more to suggest lactose malabsorption.69 The extent of elevation relates to the degree of malabsorption. 

False-Positive Results False-positive results occur rarely and are usually a consequence of the following interfering factors: • Fiber intake. Fiber should be avoided 24 hours before the test. Ingesting fiber in food or in supplements increases fermentation and hydrogen production.70–72 • Exposure to tobacco smoke. Tobacco smoke increases hydrogen levels and should be avoided immediately before and during testing.73 • Sleeping. Sleeping between breath sample collections may increase both hydrogen and methane levels.74 

False-Negative Results Breath hydrogen/methane testing has a false-negative rate of approximately 5%; the false-negative rate is 10% if only hydrogen is measured. False-negative results can occur because of the following factors: • Use of lactase supplements.55 • Use of antibiotics before the test. Antibiotics decrease the bacteria that ferment lactose.75 • Use of laxatives or enemas before the test. These decrease hydrogen and methane responses in patients with lactose malabsorption and reduce fermentation in the colon.76 • Severe diarrhea or hyperacidic colon contents. Hyperacidity inhibits the production of hydrogen and promotes the production of methane by colonic bacteria.77,78 

High Baseline Levels An elevated baseline level of breath hydrogen indicates that one or more interfering factors are present. Testing must be repeated to obtain reliable results. A baseline breath hydrogen level of greater than 10 ppm can be due to the following: • Improper fasting • Consumption of high-fiber foods the day before testing • Performance of test immediately after awakening67

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A baseline breath hydrogen level of more than 20 ppm can be due to the following: • Possible small intestine bacterial overgrowth.79 Elevated fasting levels of hydrogen occur in up to one third of patients with small intestinal bacterial overgrowth80 and may be caused by the fermentation of endogenous brush-border glycoproteins.81 • Small intestine bacterial overgrowth may elevate baseline methane readings as well.67,79,81,82 

Genomic Testing Genomic testing requires a single blood sample and avoids the diet restrictions, lengthy collection regimen, and potential for abdominal symptoms that are associated with using an oral lactose challenge. The LCT gene on chromosome 2 encodes for the enzyme LPH, and the wild type is associated with lactase nonpersistence. Lactase persistence is associated with two polymorphisms on the enhancer region upstream from LCT, C/T13910 and G/A22018. Heterozygotes are considered to have lactase persistence but with intermediate lactase activity. Homozygotes T/T13910 and G/G22018 have the lactase persistence genotype, whereas C/C and G/G homozygotes carry the wild-type nonpersistence genotype. Genomic testing, although useful, only establishes a lactase enzyme deficiency, the presence of which does not always lead to lactose intolerance symptoms. Heterozygotes, although considered carriers of lactase persistence genotyping, can have bouts of impaired lactase activity due to stress or infection, rendering intermittent bouts of lactose intolerance.83 Therefore testing for lactose malabsorption through an objective measure of lactose malabsorption, such as hydrogen breath testing, is still warranted.84 

Tissue Sampling An endoscopic biopsy of the jejunum can assess the presence of lactase as well as other disaccharidases, although this test is rarely used due to the expense and discomfort involved. Morphologically, enterocytes would not show abnormality in cases of primary lactase deficiency but may show blunting of microvilli or inflammatory changes associated with secondary causes of lactose intolerance. 

Blood Testing Lactose tolerance testing (LTT) was formerly used but has been replaced by more sensitive breath testing, as previously described. LTT required a large dose of glucose challenge, up to 50 g, which often led to abdominal symptoms that are avoided with the lower doses

used in breath testing. If the rise in serum glucose after challenge was less than 26 mg/dL during the ensuing 2 hours, then lactose maldigestion was presumed. Another similar test uses radiolabeled lactose,18 C-lactose. Although it has been shown to have the ability to differentiate between those who can digest lactose and those with maldigestion, this method has not been evaluated for its ability to identify symptoms directly related to lactose intolerance,79 and it is not available clinically. 

OTHER TYPES OF SUGAR INTOLERANCE The inability to properly digest other types of saccharides can produce symptoms similar to those caused by lactose intolerance. For this reason, it may be necessary to investigate other types of sugar intolerance, especially in patients whose clinical test results do not support a diagnosis of lactose intolerance. Commonly ingested sugars, such as fructose, sucrose, and maltose, should be considered if sugar intolerance is suspected in the presence of normal breath and genetic testing. (See Chapter 9, Bacterial Overgrowth of the Small Intestine Breath Test, for a more in-depth discussion of carbohydrate intolerance testing.) 

SUMMARY The majority of the world’s population is lactase deficient. However, lactose intolerance may not develop in all of these individuals. A comprehensive evaluation that incorporates diagnostic testing, the patient’s nutritional history, and the relationship between diet and gastrointestinal symptoms is necessary for an accurate diagnosis. Proper diagnosis of lactose intolerance allows for dietary modifications that may allow a limited amount of dairy products in some lactose-intolerant individuals. Exclusion of lactose-containing foods altogether should be done only for those requiring strict avoidance, with careful attention to the replacement of lost nutrients, such as calcium. Breath testing of hydrogen/methane production after a lactose challenge is the diagnostic method of choice.

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Srinivasan R, Minocha A. When to suspect lactose intolerance: symptomatic, ethnic, and laboratory clues. Postgrad Med. 1998;104:109–111, 115–116, 122–123. 2. Storhaug CL, Fosse SK, Fadnes LT. Country, regional, and global estimates for lactose malabsorption in adults: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2017;10:738–746. 3. Mattar R, Ferraz de Campos Mazo D, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin Exp Gastroenterol. 2012;5:113–121. 4. National Digestive Diseases Information Clearinghouse. A service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lactose Intolerance. Last updated Feb 24. https://www.niddk.nih.gov/ health-information/digestive-diseases/lactose-intolerance/definition-facts. Accessed 11/28/2010. 5. Vernia P, Di Camillo M, Marinaro V. Lactose malabsorption, irritable bowel syndrome and self-reported milk intolerance. Dig Liver Dis. 2001;33:234– 239. 6. Rusynyk RA, Still CD. Lactose intolerance. J Am Osteopath Assoc. 2001;101:S10–S12. 7. Felicilda-Reynaldo RF, Kenneally M. Digestive enzyme replacement therapy: pancreatic enzymes and lactase. Medsurg Nurs. 2016;25:182–185. 8. Park YK, Yetley EA, Calvo MS. Calcium intake levels in the United States: issues and considerations. http://www.fao.org/DOCREP/W7336T/ w7336t06.htm. Accessed 8/30/2011. 9. Lipkin M, Newmark H. Calcium and the prevention of colon cancer. J Cell Biochem. 1995;22(suppl):65–73. 10. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. dash collaborative research group. N Engl J Med. 1997;336:1117–1124. 11. Griffith LE, Guyatt GH, Cook RJ, et al. The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials. Am J Hypertens. 1999;12:84–92. 12. Lupton JR. Dairy products and colon cancer: mechanisms of the protective effect. Am J Clin Nutr. 1997;66:1065–1066. 13. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium polyp prevention study group. N Engl J Med. 1999;340:101–107. 14. Lomer MC, Parkes GC, Sanderson JD. Review article: lactose intolerance in clinical practice—myths and realities. Aliment Pharmacol Ther. 2008;27:93– 103. 15. Shaukat A, Levitt MD, Taylor BC, et al. Systematic review: effective management strategies for lactose intolerance. Ann Intern Med. 2010;152:797–803. 16. Aurisicchio LN, Pitchumoni CS. Lactose intolerance: recognizing the link between diet and discomfort. Postgrad Med. 1994;95:113–116, 119–120. 17. Berkow R, Fletcher AJ, eds. The Merck Manual. Rahway, NJ: Merck; 1992:822–830. 18. Yamada T, Alpers DH. Textbook of Gastroenterology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2003. 19. Suchy FJ, Brannon PM, Carpenter TO, et al. National Institutes of Health consensus development conference: lactose intolerance and health. Ann Intern Med. 2010;152:792–796. 20. Di Stefano M, Miceli E, Mazzocchi S, et al. Visceral hypersensitivity and intolerance symptoms in lactose malabsorption. Neurogastroenterol Motil. 2007;19:887–895. 21. Almeida JA, Kim R, Stoita A, et al. Lactose malabsorption in the elderly: role of small intestinal bacterial overgrowth. Scand J Gastroenterol. 2008;43:146–154. 22. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:233–237. 23. Ingram C, Mulcare C, Itan Y, et al. Lactose digestion and the evolutionary genetics of lactase persistence. Human Genetics. 2009;124:579–591. 24. Rasinperä H, Savilahti E, Enattah NS, et al. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut. 2004;53:1571–1576. 25. Troelsen JT. Adult-type hypolactasia and regulation of lactase expression. Biochim Biophys Acta. 2005;1723:19–32. 26. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:233–237.

27. Tishkoff SA, Reed FA, Ranciaro A, et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet. 2007;39:31–40. 28. Torniaien S, Parker MI, Homberg V, et al. Screening of variants for lactase persistence/non-persistence in populations from South Africa and Ghana. BMC Genet. 2009;10:1471–2156. 29. Piepoli A, Schirru E, Mastrorilli A, et al. Genotyping of the lactase-phlorizin hydrolase c/t-13910 polymorphisms by means of a new rapid denaturing high-performance liquid chromatography-based assay in healthy subjects and colorectal cancer patients. J Biomol Screen. 2007;12:733– 739. 30. Ingram CJ, Elamin MF, Mulcare CA, et al. A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactase persistence? Hum Genet. 2007;120:779–788. 31. Ingram C, Raga T, Tarekegn A, et al. Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group. J Molecular Evolution. 2009;69:579–588. 32. Ojetti V, Nucera Ga, Migneco A, et al. High prevalence of celiac disease in patients with lactose intolerance. Digestion. 2005;71:106–110. 33. Osterlund P, Ruotsalainen T, Peuhkuri K, et al. Lactose intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer. Clin Gastroenterol Hepatol. 2004;2:696–703. 34. Keshavarzian A, Iber FL, Dangleis MD, Cornish R. Intestinal-transit and lactose intolerance in chronic alcoholics. Am J Clin Nutr. 1986;44:70–76. 35. Henriksson R, Franzen L, Sandstrom K, et al. Effects of active addition of bacterial cultures in fermented milk to patients with chronic bowel discomfort following irradiation. Support Care Cancer. 1995;3:81–83. 36. von Tirpitz C, Kohn C, Steinkamp M, et al. Lactose intolerance in active Crohn’s disease: clinical value of duodenal lactase analysis. J Clin Gastroenterol. 2002;34:49–53. 37. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet. 2001;14:359–363. 38. Torniainen S, Freddara R, Routi T, et al. Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD). BMC Gastroenterol. 2009;9:8. 39. Heyman MB. Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006;118:1279–1286. 40. Bahna SL. Cow’s milk allergy versus cow milk intolerance. Ann Allergy Asthma Immunol. 2002;89:56–60. 41. Bernardessilva C, Pereira A, Defatimaalvesdamota G, et al. Lactase persistence/non-persistence variants, C/T_13910 and G/A_22018, as a diagnostic tool for lactose intolerance in IBS patients. Clin Chimica Acta. 2007;386:7–11. 42. Gremse DA, Nguyenduc GH, et al. Irritable bowel syndrome and lactose maldigestion in recurrent abdominal pain in childhood. South Med J. 1999;92:778–781. 43. Vernia P, Ricciardi MR, Frandina C, et al. Lactose malabsorption and irritable bowel syndrome: effect of a long-term lactose-free diet. Ital J Gastroenterol. 1995;27:117–121. 44. Rana SV, Mandal AK, Kochhar R, et al. Lactose intolerance in different types of irritable bowel syndrome in north Indians. Trop Gastroenterol. 2001;22:202–204. 45. Zaman A. Irritable bowel syndrome. Clin Cornerstone. 2002;4:22–33. 46. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr. 1988;113: 979–984. 47. Gremse DA, Greer AS, Vacik J. Abdominal pain associated with lactose ingestion in children with lactose intolerance. Clin Pediatr. 2003;42:341–345. 48. Murphy MS, Sood M, Johnson T. Use of the lactose H2 breath test to monitor mucosal healing in coeliac disease. Acta Paediatr. 2002;91:141–144. 49. Montes RG, Perman JA. Lactose intolerance. Pinpointing the source of nonspecific gastrointestinal symptoms. Postgrad Med. 1991;89:175–178, 181–184. 50. Moore BJ. Dairy foods: are they politically correct? Nutr Today. 2003;38:82– 90. 51. Newcomer AD, McGill DB, Thomas PJ. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med. 1975;293:1232– 1236.

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52. Brummer RJ, Armbrecht U, Bosaeus I, et al. The hydrogen (H2) breath test. Sampling methods and the influence of dietary fibre on fasting level. Scand J Gastroenterol. 1985;20:1007–1013. 53. Zhong Y, Yin W, Huang C. Study on the expired gas of subjects with lactose intolerance by using H2/13CO2 breath test [in Chinese]. Wei Sheng Yan Jiu. 2002;31:180–183. 54. Metz G, Jenkins DJ, Peters TJ, et al. Breath hydrogen as a diagnostic method for hypolactasia. Lancet. 1975;1:155–157. 55. Lerch MM, Rieband HC, Feldberg W. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects. Digestion. 1991;48:81–88. 56. Barillas-Mury C, Solomons NW. Test-retest reproducibility of hydrogen breath test for lactose maldigestion in preschool children. J Pediatr Gastroenterol Nutr. 1987;6:281–285. 57. Barillas-Mury C, Solomons NW. Variance in fasting breath hydrogen concentrations in Guatemalan preschool children. J Pediatr Gastroenterol Nutr. 1987;6:109–113. 58. Solomons NW, Barillas C. The cut-off criterion for a positive hydrogen breath test in children: a reappraisal. J Pediatr Gastroenterol Nutr. 1986;5:920–925. 59. Tormo R, Bertaccini A, Conde M, et al. Methane and hydrogen exhalation in normal children and in lactose malabsorption. Early Hum Dev. 2001;65(suppl):S165–S172. 60. Vernia P, Camillo MD, Marinaro V. Effect of predominant methanogenic flora on the outcome of lactose breath test in irritable bowel syndrome patients. Eur J Clin Nutr. 2003;57:1116–1119. 61. Montes RG, Saavedra JM, Perman JA. Relationship between methane production and breath hydrogen excretion in lactose-malabsorbing individuals. Dig Dis Sci. 1993;38:445–448. 62. Bond JH, Levitt MD. Quantitative measurement of lactose absorption. Gastroenterology. 1976;70:1058–1062. 63. Robb TA, Davidson GP. Two-hour lactose breath hydrogen test. J Pediatr Gastroenterol Nutr. 1987;6:481–482. 64. Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med. 1969;281:122–127. 65. Newcomer AD. Screening tests for carbohydrate malabsorption. J Pediatr Gastroenterol Nutr. 1984;3:6–8. 66. Jain NK, Patel VP, Pitchumoni CS. Efficacy of activated charcoal (AC) in reducing intestinal gas: a double blind clinical trial. Am J Gastroenterol. 1986;81:532–535. 67. Hamilton LH. Breath Tests and Gastroenterology. Milwaukee: QuinTron Instruments; 1998.

68. Cloarec D, Bornet F, Gouilloud S, et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut. 1990;31:300–304. 69. Fritz M, Siebert G, Kasper H. Dose dependence of breath hydrogen and methane in healthy volunteers after ingestion of a commercial disaccharide mixture. Palatini Br J Nutr. 1985;54:389–400. 70. Behall KM, Scholfield DJ, van der Sluijs AM. Breath hydrogen and methane expiration in men and women after oat extract consumption. J Nutr. 1998;128:79–84. 71. Behall KM, Howe JC. Breath-hydrogen production and amylose content of the diet. Am J Clin Nutr. 1997;65:1783–1789. 72. Kondo T, Nakae Y. Breath hydrogen and methane excretion produced by commercial beverages containing dietary fiber. J Gastroenterol. 1996;31:654–658. 73. Rosenthal A, Solomons NW. Time-course of cigarette smoke contamination of clinical hydrogen breath-analysis tests. Clin Chem. 1983;29:1980–1981. 74. Solomons N. Evaluation of carbohydrate absorption: the hydrogen breath test in clinical practice. Clin Nutr J. 1984;3:71–78. 75. Gilat T, Ben Hur H, Gelman-Malachi E, et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut. 1978;19:602–605. 76. Solomons NW, Garcia R, Schneider R, et al. H2 breath tests during diarrhea. Acta Paediatr Scand. 1979;68:171–172. 77. Vogelsang H, Ferenci P, Frotz S, et al. Acidic colonic microclimate—possible reason for false negative hydrogen breath tests. Gut. 1988;29:21–26. 78. Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora: studies in vivo and in vitro. J Clin Invest. 1981;67:643–650. 79. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology. 1988;95:982–988. 80. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol. 2002;97:1113–1126. 81. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterology. 1982;83:388–393. 82. Kerlin P, Wong L. Lactose tolerance despite hypolactasia in adult celiac disease. J Gastroenterol Hepatol. 1987;2:233–237. 83. Matthews SB, Waud JP, Roberts AG. Systemic lactose intolerance: a new perspective on an old problem. Postgraduate Med J. 2005;81:167–173. 84. Waud JP, Matthews SB, Campbell AK. Measurement of breath hydrogen and methane, together with lactase genotype, defines the current best practice for investigation of lactose sensitivity. Ann Clin Biochem. 2008;45: 50–58.

22 Metal Toxicity: Assessment of Exposure and Retention David Quig, PhD

OUTLINE Introduction, 187 Assessment of Toxic Metal Exposure, 188 Hair Elemental Analysis, 188 Blood Analysis: Toxic Metal Exposure, 188 Urinalysis of Toxic Elements Exposure: Unprovoked, 189 Urinalysis: Biomarkers of Renal Cadmium Toxicity, 189 Assessment of Retention: Urinalysis, Provocation Tests, 190

INTRODUCTION It is imperative that clinicians understand and apply in practice the distinction between metal toxicity, as clearly defined by standards of care, and the toxic effects of metals that may be associated with the net retention of toxic elements; it is not just a matter of semantics. The incidence of high-level exposure to toxic metals and acute poisoning/ toxicity is rare and is most commonly associated with occupational sources. Associated symptoms are well defined and accepted. A plethora of published research has clearly defined many of the specific biochemical mechanisms by which even much lower levels of metals elicit a vast array of adverse effects that can culminate in neurotoxicity, nephrotoxicity, cardiovascular and pulmonary disease, cancer, teratogenicity, and dysregulation of immune function. Despite knowledge of the adverse effects of metals on the most basic biochemical processes that may affect human health, the fact that environmental exposure with cumulative retention of “subthreshold” levels of toxic elements may warrant clinical intervention is not generally accepted by the dominant medical community. However, with respect to lead, mercury, and cadmium, a consultant to the National Institute of Environmental Health Sciences stated that the margin between the levels of exposure for people in industrialized nations and the levels of exposure that are currently recognized as producing the lowest adverse effect levels is small.1,2 The established laboratory tests accepted for a diagnosis of metal toxicity (e.g., blood lead) do not provide an estimate of the actual levels of metals that have accumulated in the body. The purpose of this chapter is to provide an overview of the various laboratory tests for the (1) objective assessment of exposure to toxic metals and (2) estimation of net retention of toxic metals. It is beyond the scope of this chapter to discuss the sources and symptoms associated with net retention of the most commonly encountered metals. (See Crinnion and Pizzorno, Clinical Environmental Medicine, Elsevier, 2018, for a comprehensive discussion of toxic metals.) Thorough reviews of these topics have been published elsewhere.3–7 The most commonly encountered toxic metals (mercury, lead, cadmium, and arsenic) are natural constituents of the earth’s crust,

EDTA, 190 DMPS, 190 DMSA, 191 Nonpharmaceutical Agents, 191 Fecal Metals Analysis, 191 Conclusion, 192

but their increasing abundance in air, water, and surface soil results primarily from industrialization and energy production (pollution). Consequently, the environment today has become contaminated to the point that everyone, regardless of occupation, is at higher risk for at least long-term, low-level exposure to toxic metals. However, consistent with the basic principles of toxicology, confirmation of exposure is by no means valid documentation of clinically significant retention. In reality, the toxic effects of metals for an individual are exhibited when the level of retention exceeds physiological tolerance, and net retention (body burden) is determined by the relative rates of toxic metal assimilation and excretion. Two important concepts that have been largely overlooked with respect to metal toxicity may explain the discrepancies of opinion expressed by practitioners of conventional medicine and preventive medicine. The first is the potential for the combined effects of multiple toxic metals, which can have additive, but also synergistic, adverse physiological effects (and, of course, toxic chemical exposure aggravates the problem),8,10 even in children with environmental exposures.9 This concept should be further extended to include consideration of the potential combined effects of organ toxicants and toxic metals, the total toxic load. The broad heading of “toxic chemical entities” includes not only naturally occurring and synthetic exogenous compounds but also noxious endogenous compounds derived from a severely disrupted dysbiotic or poorly functioning gastrointestinal (GI) metabolome. An additional factor is the remarkable individual variability in susceptibility or tolerance to toxic elements. Established precedence for the phenomena has been provided by such observations as the rapid contact allergic response that is elicited by mercury in a small percentage of a population.11 Individual variability in susceptibility is determined in part by genetic polymorphisms, nutritional status, and the total toxic load. The factors of multiple toxicants and individual variability impede simple interpretation of any laboratory test result for an individual patient. No single definitive test can be used to diagnose the toxic effects of excessive retention of toxic elements; any test result must be interpreted in conjunction with a thorough review of a patient’s physical findings,

187

188

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Primary and Adjunctive Diagnostic Procedures

exposure history, and symptoms. However, the symptoms associated with toxic metal retention appear to be diverse and rather nondescript, and they may not be fully expressed until later in life. Clear examples of such latency of symptom expression have been provided for lead and hypertension12 and cardiovascular mortality.13 Therefore to address the needs of clinicians who focus on preventive medicine as opposed to crisis management, the following review of laboratory tests emphasizes testing that has greater sensitivity with respect to the detection of the bioaccumulation of toxic elements. Emphasis has been placed on the distinction between testing that is most appropriate for assessment of exposure versus net retention. 

ASSESSMENT OF TOXIC METAL EXPOSURE Hair Elemental Analysis When performed properly, hair elemental analysis can serve as a qualitative screening test for exposure to toxic metals, but it is not a reliable method for the diagnosis of metal toxicity or net retention. Hair is an excretory tissue that can provide a cumulative record of bioavailable trace elements in the body, and the hair content of mercury, arsenic, lead, and thallium has been used as evidence for the cause of death.14 Once metals are incorporated into growing hair, there is no back exchange into the body; the concentration of metals in hair is usually far greater than that in blood or urine. The length of the hair specimen analyzed dictates the duration of time during which exposure occurred, and segmental analysis of hair can be used forensically to estimate the temporal course of exposure. A study of the lead and mercury content of hair from a long-deceased president of the United States was performed at the Armed Forces Institute of Pathology in Washington, DC, exemplifying the potential utility of hair analysis for exposure to toxic metals.15 Detection of toxic metals in hair actually predates that in blood and urine.16 A growing number of peer-reviewed publications support the value of elemental analysis of hair specimens for the detection of exposure to toxins, and some national laboratories have been performing hair elemental analysis for mercury, lead, and arsenic for years. Arsenic in both hair and urine confirmed arsenic exposure from an arsenical pesticide in an individual with peripheral neuropathy and macrocytosis.17 Hair levels of lead, manganese, cadmium, and other toxic metals have been correlated with psychological conditions and deviant or violent behaviors.18 Lead, cadmium, and mercury levels in children’s hair have been inversely correlated with childhood intelligence. Hair analysis has been used to identify historical as opposed to current exposure to lead.20 School children with relatively high levels of lead in their hair had slower reaction times and less flexibility in changing their focus of attention than children with relatively low concentrations of lead in their hair.21 More recently, hair levels of lead and barium were found to be higher in rural populations in relation to their proximity to oil fields (contaminated water) in the Thar Jath oil fields in South Sudan.19 The Agency for Toxic Substances and Disease Registry (ATSDRss), the U.S. Environmental Protection Agency, and the National Academy of Sciences recognize the scientific validity of hair mercury levels as an indicator of maternal and fetal exposure to methylmercury. In a cognitive performance study of children in the Faroe Islands, there were detectable effects on brain function in the children whose mothers had elevated levels of hair mercury.22 A history of fish consumption and mercury in hair samples are considered the best indicators of human exposure to methylmercury.23 Fish consumption among Scandinavian25 and Tyrrhenian men,26 Amazonian children,27 and people from the Minamata Bay area15 and the San Francisco Bay area24 was positively correlated with hair and blood mercury levels. Note that hair elemental analysis definitely provides useful information about exposure to methylmercury (fish consumption);

however, it is not nearly as useful for disclosing information about exposure to inorganic mercury as derived from dental amalgams.15 The concentration of methylmercury in hair is about 300 times higher than that in blood.28 In sharp contrast, about 75% of total hair arsenic is present in the inorganic form.29 Although an increasing number of peer-reviewed published studies support the clinical utility of elemental analysis of hair for the assessment of exposure to specific toxic metal forms, some considerations prevent its acceptance by governmental agencies in the United States. In June 2001, the Agency for Toxic Substances and Disease Registry (ATSDR) convened a panel of scientists with some expertise in hair analysis or risk assessment to explore “the state of the science of hair analysis.”30 Overall, the discussion was objective and focused on the existing scientific data. In a summary statement from the meeting, it was concluded that “in general, hair analysis results can provide limited qualitative insights into environmental exposures and rarely can answer questions about potential health effects.”27 The primary concerns raised by the group pertained to uncertainties about the quantitative relationship among the actual “internal dose,” the rate of incorporation into hair, and the current lack of well-established data to enable one to predict potential health effects for a given concentration of a specific metal in hair. Such criticisms are irrelevant to those who understand the limitations of hair elemental analysis. Overinterpretation of the results of elemental analysis of hair is a serious concern shared by science-based laboratories and astute clinicians as well as the ATSDR. It should be kept in mind that the ATSDR has been interested in the use of hair analysis as an initial screening tool for inexpensive and noninvasive monitoring of populations in the vicinity of known sites of contamination. The goal of the ATSDR to be able to use hair elemental analysis as confirmation of toxicity is quite different from the use of the test in preventive or environmental medicine to provide an initial indication of exposure. The consensus report by the ATSDR is consistent with the aforementioned statement that hair analysis can provide some qualitative information about exposure to toxic metals but does not provide a basis for the diagnosis of metal toxicity. As such, hair analysis may be helpful to clinicians as a step toward identifying potential health problems that may be associated with toxic metal exposures before overt symptoms are expressed. Further testing should be performed before treatment options are considered. The clinician should be wary of laboratories that perform hair analysis as a vehicle to sell nutritional supplements and should be aware of interlaboratory variation.31 Clinicians are encouraged to use only laboratories that can validate their certification or accreditation and incorporate state-of-the-art methodologies for washing, digesting, and analyzing hair specimens.32 Appropriate quality control characteristics and the validation of the establishment of reference ranges, accuracy, precision, and reliability of state-of-the-art hair analysis have been described.33-35 

Blood Analysis: Toxic Metal Exposure For the most commonly encountered toxic metals, the current standard for diagnosis of metal toxicity is abnormally high concentrations in whole blood or urine (e.g., thallium, arsenic). However, blood analysis for toxic metals is a better indicator of exposure than toxicity in most cases. Distribution of metals, such as lead, in the body has been long recognized as initially dependent on the rate of delivery via the blood to various tissues and organs.36 Subsequent redistribution then depends on the relative affinities of tissues for the metals and toxicokinetics that can vary markedly among individuals. Tissue affinities for metals are determined in large part by the high relative intracellular concentrations of reduced glutathione and metallothionein.37

CHAPTER 22 

Metal Toxicity: Assessment of Exposure and Retention

Furthermore, blood levels can fluctuate considerably with intermittent exposure and assimilation. Thus as stated by the ATSDR and the Centers for Disease Control and Prevention, the concentration of lead in the blood reflects mainly the exposure history of the previous few months and does not necessarily reflect the larger burden and much slower elimination kinetics of lead in bone.10 Examining kinetic models of metal metabolism shows that the blood compartment has the shortest half-life. Metals leave blood by excretion (urine, bile, and sweat) and transfer to tissues. The retention by tissues, such as bone, kidneys, and brain, accounts for the much longer biological half-lives of most toxic metals in the body. This simple concept has been clearly demonstrated in numerous studies and in the Physician’s Desk Reference.29 Adult and pediatric patients who were diagnosed with lead toxicity on the basis of elevated blood lead values exhibited marked reductions in blood lead levels after chelation therapy with Chemet (DMSA). However, 2 weeks after cessation of chelation, blood lead levels rebounded to between 60% and 85% of pretreatment levels (the rebound effect has been associated with all pharmacological chelators). The relationship between blood lead levels and the quantity of lead excreted in urine after calcium disodium edetate (Ca-EDT) DMSA chelation is nonlinear, in that arithmetic increases in blood lead are associated with exponential increases in urine lead excretion.1,39 Under extreme conditions of grossly excessive retention of metals (long-term occupational exposure), the equilibrium between tissue stores and blood can result in blood metal levels that are at or above the established threshold values for the diagnosis of metal toxicity but still do not indicate the extent of total body metal retention. The currently established standard of blood lead levels for the assessment of lead toxicity in children is disturbing because no minimum response levels have been established for lead because a threshold has yet to be defined for the most sensitive effect of lead neurotoxicity.45 Interestingly, separation of blood into the plasma versus red blood cell components can provide valuable information to the clinician about the primary sources of exposure to mercury. Approximately 95% of methylmercury, most commonly derived from contaminated fish, partitions into red blood cells,46,47 whereas about 90% of inorganic mercury (amalgams, occupational exposure) is found in the plasma compartment bound to albumin, cysteine, and nonspecific proteins.32 Because the first step in successful detoxification is to remove the source of exposure, documentation of the primary source of exposure to mercury can be instrumental for efficient detoxification. Blood arsenic levels, albeit with a very short half-life (approximately 6 hours), reflect exposure to inorganic arsenic but not dietary organic arsenic (shellfish), which is rapidly excreted in the urine.48,92 The blood levels of metals derived from orthopedic metal implants have come to the forefront, especially with respect to metal-on-metal (M/M) total hip arthroplasty. All patients with such M/M prostheses will have elevated levels of cobalt and chromium.40,41 The wear-related release of the metal debris has been causally associated with not only local tissue damage42 but also remote adverse effects on a wide array of physiological/biochemical processes and functions.43,44 

Urinalysis of Toxic Elements Exposure: Unprovoked In general, urinalysis for toxic metals does not provide a scientifically valid basis for the diagnosis of metal toxicity. However, in some cases it provides an indication of very recent or ongoing exposure. Such is not necessarily the case for lead because urinary lead is generally not a useful biomarker to estimate low-level exposure. However, elevated urinary lead-chelate complexes resulting from the EDTA Ca-EDTA or

189

DMSA mobilization test provide a good means to estimate net retention of lead. A different scenario exists for organic arsenic and inorganic and methylmercury. The most commonly accepted biomarker for exposure to inorganic mercury is the urinary level of inorganic mercury.49 However, the World Health Organization (WHO) standard for occupational exposure is very high (50 mcg/g creatinine).50 This high standard has been challenged because neurological impairment has been reported for occupationally exposed subjects51,52 whose urinary mercury levels were well below the WHO standard. Evidence that urinary mercury levels are indicative of exposure to implanted mercury amalgams has also been published.53 In a study of more than 1000 Vietnamera veterans reported by the National Institute of Dental Research, a highly statistically significant correlation was detected between the level of amalgam exposure and urinary mercury levels. Several other studies have reported an association between amalgam exposure and urinary mercury levels.54,56-58 Elevated levels of urinary arsenic have been detected in workers during periods of occupational exposure, including copper smelting, spraying of insecticides or herbicides, and application of wood treatments.61 Arsenic can be markedly and transiently elevated in individuals within 48 hours after consumption of shellfish that contain high levels of relatively nontoxic species of organic arsenic (e.g., arsenobetaine, arsenocholine).62 Urinary mercury is frequently elevated in consumers who regularly consume fish.15,63 Therefore analysis of an unprovoked urine specimen is highly recommended to avoid alarmism and misinterpretation of the results of a urinary metals provocation test. Patients should be instructed to abstain from the consumption of fish and shellfish for about a week before a chelation challenge is performed. Elevated urinary values of arsenic and mercury associated with the specific dietary and occupational conditions reflect recent or ongoing high-level exposure but are not necessarily reflective of the body burden of the specific elements. Although blood metal levels reflect transient transport in the body, urinary levels qualitatively reflect excretion of an unknown fraction of the total body pools of assimilated metals. 

Urinalysis: Biomarkers of Renal Cadmium Toxicity Toxic metals such as cadmium, mercury, and lead are known to be nephrotoxic at high levels of assimilation. Cadmium is of particular concern because of its exceedingly long residence time in the kidneys.64 Therefore in addition to urine levels of cadmium, urinary biomarkers of renal damage should be assessed for documentation of cadmium toxicity. Early markers of cadmium-induced renal damage include proteinuria, glucosuria, aminoaciduria, hypercalciuria, and polyuria.65 Sensitive urinary biomarkers for more advanced cadmium-induced renal tubular damage include elevated levels of the low-molecular-weight protein β2-microglobulin, retinalbinding protein, N-acetyl-β-d-glucosaminidase (NAG), and Cystatin C (especially in patients where serum creatinine may be misleading (e.g., very obese, elderly, or malnourished patients).66 Abnormal urinary levels of NAG have also been reported in association with markedly high urinary mercury levels (35 mcg/g creatinine) in chlor­ alkali workers with long-term exposure to inorganic mercury.67 It is noteworthy that the urinary NAG levels were correlated with urinary mercury and integrated dose of exposure but not with concurrently measured blood mercury levels.53 Thus it appears that assessment of urinary biomarkers of renal damage may be useful in the diagnosis of toxicity in cases of very high exposure to cadmium and perhaps mercury. However, negative findings for the renal biomarkers do not exclude the possibility of related nephrotoxicity retention that is most commonly encountered in general clinical practice. 

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Primary and Adjunctive Diagnostic Procedures

ASSESSMENT OF RETENTION: URINALYSIS, PROVOCATION TESTS The best currently available method to estimate the level of retention of toxic metals in the body is urinalysis for toxic metals after the administration of chelating agents.55 In the 1970s, the value of a standardized calcium-disodium EDTA (Ca-Na2-EDTA) provocative test was recognized as sensitive to determine the mobile and potentially toxic body lead stores and to assess response to chelation therapy in pediatric patients with high blood lead levels.68–70 Subsequently, Markowitz and Rosen61 described the results of a comparable, yet more convenient test that would permit use in a greater number of qualifying patients. The concept and value of using metal complexing agents to estimate the net retention of readily accessible toxic elements has gained some acceptance, but it is not accepted by the American College of Medical Toxicology.59 That position is in direct conflict with a renowned nephrologist who has stated that “the best measure for assessing the total accumulation of lead in the body is the calcium disodium EDTA lead mobilization test.”60 Several other pharmaceutical agents are widely used for this purpose. The most commonly used pharmaceutical agents are Ca-Na2-EDTA, Dimaval-(RS)-2,3-dimercapto-propropane-1 sulfonate (DMPS), and mes-2,3-dimercaptosuccinic acid (DMSA). Nonpharmaceutical compounds that have also been used as possible provocation agents include N-acetyl-cysteine (N-AC) and potassium-citrate (K-citrate).72 The latter compounds are not chelators by definition and have not been studied extensively or compared with the efficacy of the well-established Ca-EDTA lead mobilization test.

EDTA Ca-Na2-EDTA is the only form of EDTA approved for lead decorporation by the U.S. Food and Drug Administration (FDA). It has been used for decades as the provocation agent and therapeutic agent of choice for patients with high blood lead levels. The true chelator is also well known to be effective for increasing the urinary excretion of antimony, gadolinium, iron, cobalt, trivalent chromium, copper, nickel, cadmium, and manganese.73 Ca-EDTA also has a high affinity for zinc and, if not used properly, can cause zinc depletion. Clinicians are strongly encouraged to assess glomerular function before use (Ca-EDTA mobilized metals are excreted in the urine). Before attempting to embark on the safe and effective use of Ca-EDTA, clinicians should attend specific training courses. Although the “slow-push” Ca-Na2-EDTA protocol introduced in the United States appears to be effective for increasing the urinary excretion of lead,74 it has not been formally evaluated for safety. Ca-EDTA is not an effective chelator of mercury as are the dithiol metal complexing agents discussed next. 

DMPS DMPS appears to be the most productive agent for the mobilization of mercury, as determined in vitro75 and in a comparative study during the Iraqi mercury crisis, in which people were acutely poisoned after consumption of grains contaminated with a methylmercury-containing fungicide.76 More relevant to the typically encountered clinical situation, a DMPS provocation study was conducted with volunteer college students.77 Subjects with and without amalgam fillings were given 300 mg DMPS (orally), and all urine was collected over the subsequent 9 hours. DMPS raised mean urinary mercury for the nonamalgam group from 0.27 to 5.1 mcg and that of the amalgam group from 0.7 to 17.2 mcg over the 9-hour period. A highly significant positive correlation was detected

between the amount of mercury excreted after the DMPS challenge and amalgam surface area. An additional study supports the value of provocation testing for people occupationally exposed to mercury vapors. A comparison of urinary mercury levels was made before and after oral administration of a 300-mg dose of DMPS to dental technicians, dentists, and nonoccupationally exposed controls.46 Unprovoked urine mercury levels were comparable for dental technicians and dentists and were about five times higher than those in controls. Compared with preprovocation values, DMPS-induced urinary mercury (micrograms per 6 hours) increased by a factor of 87, 49, and 34 for the technicians, dentists, and controls, respectively. Post-DMPS urinary mercury levels were 16 and 6 times higher than in controls for the technicians and dentists, respectively. The group’s mean urinary mercury for the technicians after DMPS was 424 ± 85 mcg/6 h. The baseline urinary coproporphyrin level, which is an established biomarker of mercury-induced disruption of heme biosynthesis, was significantly correlated with urinary mercury levels after DMPS but was not correlated with baseline urinary mercury levels. The researchers concluded that post-DMPS urinary mercury levels were better indicators of exposure and retention than unprovoked urinary mercury levels. The pharmacokinetics of DMPS have been well defined,78,79 and the efficacy of DMPS for detoxification of mercury,80 arsenic,81 and lead (pediatric)82 has been documented. Although DMPS is not approved by the FDA, it is registered in Germany with the German Drug Regulatory Authorities and is available in the oral form without a prescription.68 DMPS is no longer available to clinicians in the US. DMPS is associated with a very low incidence of serious side effects,68 and its safety in general was evident from the observations made during the course of extensive IV administration (250 mg every 4 hours for 12 consecutive days) in a young woman who had severe arsenic toxicity.71 The most commonly reported side effects associated with DMPS are nausea, weakness, vertigo, chills, fever, cutaneous reactions/itching, erythema multiforme, and elevations of transaminases.69,71,72 An extensive review of the German literature about the pharmacokinetics, affinities for various metals, and side effects of DMPS is available.72 The recommended IV dose of DMPS is 3 to 5 mg/kg (not to exceed 250 mg to avoid hypotension). A detailed description of an extensively used oral DMPS provocation protocol has been presented,68 as well as an IV DMPS provocation protocol.6 To establish the basal urinary rate of metal excretion, the patient is instructed to fast overnight and collect a first-morning urine specimen. In the morning, with an empty stomach and after the bladder is emptied, the patient is given about 300 mg DMPS (5 to 10 mg/kg) orally or 3 to 5 mg/kg intravenously. All urine is collected for the subsequent 6 hours.68 A light meal (no seafood or fish) may be consumed about 2 hours after oral ingestion, and fluid consumption is encouraged. The specific laboratory instructions should be followed for shipping the specimen. Metals mobilized by DMPS are excreted primarily by the kidney and to a much lesser extent by the liver (biliary/fecal).68 Equilibrium and stability constants (in vitro) for various DMPS– metal complexes have been presented.83 In the clinical setting, DMPS is effective for the mobilization and excretion of bismuth, mercury (organic and inorganic), copper, lead, arsenic, antimony, nickel, tin, tungsten, and gold but does not affect thallium, aluminum, or uranium excretion. In the majority of adult patients, mercury is the predominant metal excreted after DMPS, and elevation of copper is normal (about five times higher than the preprovoked urine level). As mercury levels decline during detoxification therapy, it is common to see increased urinary levels of other metals, such as lead and tin, with subsequent challenges. The shifting pattern of the metal species excreted is based on a

CHAPTER 22 

Metal Toxicity: Assessment of Exposure and Retention

combination of affinities of DMPS for the different metals as well as on mass competition for metal-binding sites. There are no well-established guidelines for the interpretation of the results of the DMPS challenge test. Therefore conclusions about toxicity cannot be made from the DMPS test results alone. Consideration has to be given to the overall medical examination, medical and exposure history, and presenting symptoms. If a decision is made to proceed with some form of detoxification therapy, the initial challenge result can serve as a reference point against which subsequent challenge results can be compared with to evaluate the efficacy of treatment. The levels of other toxic metals excreted should always be considered, and one should note that DMPS does not provide direct information as to the level of mercury present in the central nervous system. It is beyond the scope of this chapter to discuss protocols for metal detoxification, but it is emphasized that if a pharmaceutical metal complexing agent is to be used, the glomerular filtration rate must be assessed before initiation and periodically during the therapy. Some clinicians use transdermal DMPS for both diagnosis and treatment. However, one study found no measurable presence in blood or urinary DMPS after a standard dose.84 

DMSA Another dithiol metal-complexing agent, DMSA, is also widely used for provocation testing, as well as detoxification therapy for lead, mercury species, and other sulfhydryl reactive metals (e.g., arsenic, antimony). Several studies demonstrated the effectiveness of DMSA to increase the urinary excretion of lead85–87 and mercury and decrease the blood levels of these metals.30,88–90 DMSA was approved by the FDA for lead detoxification in children with lead poisoning and is an agent of choice for lead detoxification in children and adults. DMSA appears to be considered by some to be the “new chelator” for lead. Only about 20% of orally administered DMSA is systemically available after a single dose.29 DMSA, when used in conjunction with Ca-Na2-EDTA, increases cumulative urinary lead excretion and ameliorates the Ca-EDTA–mediated redistribution of lead to soft tissues.81,91 DMSA is restricted to the extracellular compartment and does not have direct access to the elements retained in the cells or interstitial fluid, and it does not appear to cross a healthy blood–brain barrier. In rodent models, however, DMSA has been demonstrated to be effective in decreasing the levels of lead and mercury in the brain.77,82,83,85 Animal studies also indicated greater efficacy of DMSA for lead detoxification when concomitantly administered with antioxidants.78,79 This is true for all bona fide metal-complexing and metal-chelating agents. N-acetyl cysteine alone appears to enhance lead excretion to a much lesser degree than DMSA, but in contrast, the potential effects of α-lipoic acid alone are equivocal. To date, no reliable studies have been published to indicate that lipoic acid is an effective metal-binding agent that has a net effect on metal excretion in humans, and the potential for lipoic acid–induced mercury redistribution, particularly to the brain, is a significant consideration.86 DMSA is generally well tolerated with common but mild side effects, including GI bloating and/or gas, occasional loose stools, and skin rash. Assessment of liver enzyme levels is recommended before and periodically during extended administration. Compared with DMPS and Ca-EDTA, DMSA has minimal effects on essential elements such as copper and zinc. DMSA is excreted almost exclusively as a mixed disulfide with two molecules of cysteine.87 Thorough reviews of the pharmacokinetics and clinical use of DMSA have been presented.6,68,69,88 It should be noted that there is a tremendous difference between the DMSA protocol described for acute lead poisoning76 and that commonly used for chronic lead retention. Various protocols for DMSA provocation testing have been suggested.6,89 However, a convenient and productive provocation protocol has been described that entails giving a single dose of DMSA orally

191

(30 mg/kg, not more than 2 g) on an empty stomach and bladder followed by collection of all urine for the subsequent 6 hours.62 The peak rate of excretion of metals occurs after about 3 hours. The protocol is well tolerated, enhances compliance, and significantly reduces exposure to the compound. Patients should be advised in advance that their urine will transiently have a foul, sulfurous odor and that transient GI inconvenience may occur. 

Nonpharmaceutical Agents Nonpharmaceutical compounds, such as N-acetyl-l-cysteine (N-AC) and potassium citrate (K-citrate), have been tested for efficacy as provocation agents for mercury in one published study.62 Urinary mercury levels, expressed as micrograms per liter, were compared before and after a single oral dose of N-AC (30 mg/kg), K-citrate (5 g in 200 mL water), DMSA (30 mg/kg), or DMPS (Unithiol, 250 mg in 5 mL water). Basal urinary mercury levels (about 5 ug/L) were comparable for all of the treatment groups, each of which contained 16 to 65 multisymptomatic subjects. All subjects either had dental amalgams or had recently undergone removal of amalgams. Urine was collected for 3 hours after the challenge compounds were given, except that urine was collected for only 2 hours after the DMPS. The different collection time for the DMPS prohibits valid comparisons of the effects of the other agents. The high bolus doses of N-AC and K-citrate significantly increased urinary mercury, by 131% and 83%, respectively, compared with basal values. Under these conditions of different collection times, DMSA and DMPS increased mercury excretion by 163% and 135%, respectively. No mention was made of the urine volumes associated with the different test groups, and, clearly, the data would have been easier to interpret had the results been standardized per gram urine creatinine. Grossly misleading values for urinary metals can be associated with the expression of excreted metals per unit volume because urinary output can vary considerably. No other data are currently available to permit further evaluation of the value of the nonpharmaceutical compounds as provocation agents. These two compounds also should be tested in animal models to determine whether they are associated with significant redistribution of metals among various tissues because neither is a true chelator, and their stability constants are relatively low. Currently, no definitive studies are available to assess the utility of parentally administered reduced glutathione as a direct metal-complexing agent. A final note about other routes of administration of various authentic and potential metal detoxification agents, particularly with respect to provocation testing, is that the author has not been able to find any published research addressing the systemic bioavailability or efficacy of any agent that is given via a transdermal delivery system. 

FECAL METALS ANALYSIS Several toxic metals, including mercury, lead, thallium, and cadmium, are naturally excreted primarily or partially in bile. Therefore under certain conditions, analysis of fecal metals, without provocation, may provide at least qualitative information about the rate of biliary excretion of assimilated metals. However, contaminated foods present a significant source of exposure to metals, and metals that have not been assimilated by the gastrointestinal tract can contribute overwhelmingly to the total amount of metals measured in a fecal specimen. In addition to dietary contamination, fecal mercury is very much influenced by the amount of mercury that is present in the mouth in the form of mercury amalgams.90 Fecal mercury concentrations, expressed per gram of dry weight, are roughly an order of magnitude higher in people who have an average of six to eight medium-sized amalgams than in individuals who are amalgam-free.90 Day-today variability in fecal mercury levels in amalgam bearers is remarkably small. Fecal mercury levels are highly correlated with the number of

192

SECTION 2 

Primary and Adjunctive Diagnostic Procedures

amalgams (Fig. 22.1). Further, it has been demonstrated that fecal mercury levels decline significantly after extraction of amalgams.91 Therefore levels of fecal metals generally are more a representation of exposure to metals than an indication of total body retention. Current research efforts are focusing on the identification of metal-complexing agents or phytonutrients that increase the biliary/fecal excretion of metals. Fecal metals have been analyzed in autistic children (n = 54), and, on average, metal levels were significantly higher compared with those in age-matched, neurotypical controls (n = 83).83 The reason for the higher levels in association with autism is not known, and pica is a possible issue that may contribute to higher levels of exposure in patients with autism. 

CONCLUSION Long-term, low-level exposure to environmental toxins is a growing global problem, and evidence is accumulating to link the bioaccumulation of toxic metals in humans to subtle and overt long-term toxic effects, poor health, and substantially increased disease risk. Increasing numbers of patients dissatisfied with the care provided by clinicians who rely only on methods for the assessment of acute metal poisoning are seeking out clinicians who are

aware of the value of tools that are yet to be accepted for the assessment of subacute metal toxicity. Analyses of metals in hair, blood, and urine all have advantages and disadvantages, and no single currently available laboratory test can unequivocally permit a valid diagnosis of “subclinical” metal toxicity. The results of the various tests discussed in this chapter, along with a complete medical examination, exposure history, and other findings, can be used to design a comprehensive therapeutic detoxification program. Table 22.1 provides an overview of the value of the various tests for assessing a patient’s potential problem with toxic elements. To close, it is emphasized that there is a need for better chelating agents that have much greater volumes of distribution and the ability to safely cross a normal blood–brain barrier and directly remove neurotoxic elements from the central nervous system. Perhaps research toward finding a cure for Parkinson’s disease or premature dementia will provide such agents.

REFERENCES See www.expertconsult.com for a complete list of references.

0.644

0.800 0.600 0.315

Conc. 0.400 (ppm) 0.200

0.074

0.038

0.000 None

1-3

4-7

8-12

Number of amalgams Fig. 22.1  Fecal mercury levels versus the number of dental amalgams. Fecal mercury (microgram per kilogram dry weight) was plotted against number of amalgams for 200 subjects. (Data from Bass DA, Urek K, Quig D. Measurement of mercury in feces. Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999.)

TABLE 22.1  Summary of the Potential Clinical Value of Hair Analysis and Urinalysis URINE (RETENTION) Metal/Metalloid

Hair (exposure)

No Provocation

DMSA

DMPS

Ca-Na2-EDTA

Aluminum Antimony Arsenic Cadmium Inorganic mercury Iron Lead Nickel Organic mercury Tin Tungsten Uranium

Fair Good Inorganic, Good Fair Poor to fair Poor Good Poor Excellent Poor Good Good

Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor

Poor Good Good Fair Excellent Poor Good Fair Excellent Good Fair Poor

Poor Good Excellent Fair Excellent Poor Fair Fair Excellent Good Fair Poor

Fair, best with deferoxamine Good Poor Good with IV GSH Poor Good, best with deferoxamine Excellent Good Poor Good Poor Poor

Summary of the potential value of hair analysis (exposure) and the most commonly used provocation agents used in conjunction with urinalysis for the detection of retention of specific metals. The qualitative guidelines are based on the author’s perception of affinities (in vivo) derived from the examination of thousands of test results and stability constants as determined under highly defined conditions in vitro. The information provided does not include the potential use of adjunctive agents and/or protocols and does not cover all known metal complexing agents. Ca-Na2-EDTA, calcium-disodium ethylenediaminetetraacetic acid; DMPS, Dimaval-(RS)-2,3-dimercapto-propane-1 sulfonate; DMSA, meso-2,3dimercaptosuccinic acid; GSH, glutathione; IV, intravenous.

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73. Dimival (DMPS). Summary of Scientific Literature. Houston: Heyltex Corp.; 1991. 74. Graziano JH, Siris ES, LoIacono NJ, et al. 2,3-dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther. 1985;37:431–438. 75. Grandjean P, Jacobsen IA, Jorgensen PJ. Chronic lead poisoning treated with dimercaptosuccinic acid. Pharmacol Toxicol. 1991;68:266–269. 76. Roels HA, Boeckx M, Ceulemans E. Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med. 1991;48:247–253. 77. Smith D, Bayer L, Strupp B. Efficiency of succimer chelation for reducing brain lead levels in a rodent model. Environ Res. 1998;78:168–176. 78. Pande M, Mehta A, Pant BP, et al. Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication. Environ Toxicol Pharmacol. 2001;9:173–184. 79. Pande M, Flora SJS. Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimer in rats. Toxicology. 2002;177:187–196. 80. Lee B, Schwartz BS, Stewart W, et al. Provocation chelation with DMSA and EDTA: evidence for differential access to lead storage sites. Occup Environ Med. 1995;52:13–19. 81. Besunder JB, Super DM, Anderson RL. Comparison of dimercaptosuccinic acid and calcium disodium ethylenediaminetetraacetic acid versus dimercaptopropanol and ethylenediaminetetraacetic acid in children with lead poisoning. J Pediatr. 1997;130:966–971. 82. Aaseth J. Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropane sulfate. Analyst. 1995;120:853– 854. 83. Jones MM, Singh PK, Kostial K, et al. Comparative in vivo lead mobilization with meso- and rac-2,3-dimercapto-succinic acids in Albino Wistar rats. Pharmacol Toxicol. 1997;186:182–186. 84. Cohen JP, Ruha AM, Curry SC, et al. Plasma and urine dimercaptopropanesulfonate concentrations after dermal application of transdermal DMPS (TD-DMPS). J Med Toxicol. 2013;9(1):9–15. PMID: 23143832. 85. Gong Z, Evans HL. Effects of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead-induced neurotoxicity in the rat. Toxicol Appl Pharmacol. 1997;144:205–214. 86. Gregus Z, Stein AF, Varga F, et al. Effect of lipoic acid on biliary excretion of glutathione and metals. Toxicol Appl Pharmacol. 1992;114:88–96. 87. Maiorino RM, Aposhian MM, Xu ZF, et al. Determination and metabolism of thiol chelating agents. XV. The meso-2,3-dimercaptosuccinic acid-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Therap. 1993;267:1221–1226. 88. Miller A. Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity. Altern Med Rev. 1998;3:199–207. 89. Frumkin H, Manning CC, Williams PL, et al. Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure? Environ Health Persp. 2001;109:167–171. 90. Bass DA, Urek K, Quig D. Measurement of mercury in feces. Poster presented at American Association of Clinical Chemistry Conference, July 25-29. New Orleans; 1999. 91. Bjorkman L, Sandborg-Englund G, Ekstrand J. Mercury in saliva and feces after removal of amalgam fillings. Toxicol Appl Pharmacol. 1997;144:156–162. 92. Apostoli P, Bartoli D, Alessio L, et al. Biological monitoring of occupational exposure to inorganic arsenic. Occup Environ Med. 1999;56:825–832.

23 Mineral Status Evaluation Andrea Gruszecki, ND

OUTLINE Introduction, 193 Specimen Selection, 193 Blood, 193 Urine, 194 Hair, 194 Collection Equipment, 194 Preanalytical Variables, 194 Methodology, 194 Minerals and Disease, 194 Essential Macrominerals, 195 Calcium, 195 Chloride, 196 Magnesium, 196 Phosphorus, 197 Potassium, 197 Sodium, 198

Essential Microminerals, 199 Copper, 199 Iodine, 199 Iron, 200 Manganese, 202 Molybdenum, 202 Selenium, 203 Zinc, 203 Potentially Essential Minerals, 204 Bromine, 204 Chromium, 205 Fluorine, 205 Lithium, 206 Vanadium, 206 Conclusion, 206

INTRODUCTION

SPECIMEN SELECTION

Minerals are inorganic elements found in the earth’s crust; they are found in soil and water in varying proportions. The therapeutic effect of minerals has been recognized for more than 2000 years in Asian medicine1 and Western civilization. As early as the 2nd century BC, salt was mixed in vinegar with other spices and prescribed for various health conditions.2 The Native American Dine’ (Navajo) people traditionally used juniper ash in recipes to maintain their health; juniper ash is now recognized as a source of calcium.3 In Europe, calcium was first recognized as an essential element (for fowl) in 1790 by Dr. George Fordyce, and iodine was first recognized as a component of thyroxine by chemist Eugen Baumann in 1896.4 Scientific studies assessing the bioavailability of minerals in humans first appeared in the literature in the 1960s,5,6,7 and over the ensuing years, it became clear that minerals play an important role in the biochemistry of the human body.8,9 The human body may contain over 60 elements; currently, 15 of these elements are considered essential. Although up to 25 elements may be considered functional in human physiology, the question of which elements are essential for human life and health remains unresolved for some of the micromineral (“trace”) elements.10 Either a deficiency or an excess of physiologically active minerals may have deleterious effects on multiple enzyme systems, nerve tissues, and organs, including the brain, heart, thyroid, liver, kidneys, and skin. Reliable assessments of mineral element status are required to evaluate and monitor a patient’s mineral status.11 Analytical considerations for assessment may include specimen selection, collection equipment, preanalytical variables, and methodology.12 

The majority of nutritional elements are best evaluated in blood or urine.13 Hair may be useful in the determination of some mineral element deficiencies.14 (See Chapter 16, Hair Mineral Analysis, for a critical review of the research.)

Blood If blood is selected as the specimen type, further consideration should be given to which compartment of blood (serum, cell, or both) is required for accurate evaluation. For example, the cations sodium, potassium, calcium, and chloride are important extracellular components of the blood’s serum compartment. Clinically significant electrolyte abnormalities are common with poor oral intake, age over 65, alcoholism, diuretic use, and/or recent history of electrolyte abnormality. These clinically present with symptoms such as vomiting, chronic hypertension, recent seizure, and/or muscle weakness.15 Urinary electrolytes are more commonly analyzed in hospital settings and may provide insight regarding volume status, hyponatremia, acute kidney injury, metabolic alkalosis, hypokalemia, and urine anion gap (net charge).16 The use of older diuretic medications may also disrupt electrolyte balance and influence the selection of specimens.17 Recent dietary intake may rapidly alter serum levels of other minerals or cause wide day-to-day variation in serum or urine levels. Nutrient elements that serve as cofactors in proteins and enzymes, such as magnesium18 and zinc,19 may be primarily intracellular and may be best assessed from within blood cells (erythrocytes). Whole blood and intracellular assessments provide a longer window of exposure than serum samples

193

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because the elements within blood cells represent 60 to 120 days of nutrient element exposure. Both compartments may be assessed with a whole-blood specimen, which may be preferred if an excess of a nutrient element, such as manganese, iron, or copper, is suspected.13 

Urine Urine may be the preferred specimen for nutrients such as iodine.11 Urinary assessments require normal renal function for accuracy. Animal studies indicate that excess mineral consumption is excreted in the urine to maintain homeostasis, and excretion may rapidly decrease to reflect an insufficient intake of all minerals.20 

Hair Hair may accurately reflect a nutrient element deficiency, and some hair mineral ratios have been associated with medical disorders.21 However, the research has been inconsistent. Newer studies are confirming relationships between hair and blood for some nutrient elements and disproving others.22 Other studies are exploring the relationship between hair element concentrations and specific disease states.23 The interpretation of hair results may be confounded by the ease with which hair can be contaminated by external sources of exposure. With that proviso, hair analysis can accurately reflect exposure to, and absorption of, a limited number of elements (e.g., chromium) or deficiencies of others (e.g., copper). Research is ongoing to define the physiologic mechanisms that incorporate nutrient elements into hair tissues. Currently, for many mineral elements, a quantitative measurement from a hair sample may not represent a quantitative measurement of an ingested dose of mineral from the diet and supplements.24 In addition, external contamination may mask a deficiency or artificially increase the amount of mineral element found in a hair sample because external contaminants bind to the cysteine residues of the hair.25 The most appropriate use of hair analysis appears to be in the assessment of toxic metal exposure. The utility of hair analysis remains highly controversial; it remains an “unproven practice” according to the American Medical Association, yet it is approved by the Centers for Disease Control and Prevention for the assessment of methylmercury and other toxic metals.26 

COLLECTION EQUIPMENT Clinicians may employ whole-blood or urine analysis in the evaluation of mineral status because these fluids are the simplest and most economical to collect and transport.12,14 Tests of whole blood require no centrifugation and, like urine, require no special treatment other than collection, refrigeration, and shipping in approved containers. If samples of cellular blood components are collected, they must be centrifuged immediately per the laboratory’s instructions. If not centrifuged in a timely manner, cells may disintegrate, falsely increasing the amount of nutrient elements in the serum or plasma of the sample and falsely decreasing the amount of nutrient element available in the surviving cells. Appropriate, mineral-free containers provided by the laboratory must be used with most element collections to prevent possible leaching of elements from collection devices or shipping containers. Hair analysis has the benefit of convenience and low cost. Hair samples are noninvasive, are stable at room temperature, and require no onsite processing to improve sample quality. 

PREANALYTICAL VARIABLES Preanalytical variables in the specimen-collection process occur before the receipt of a specimen by the laboratory.12,27,28 Careful attention to collection, preparation, and shipping may decrease preanalytical errors

that may affect laboratory results. The timing of specimen collections may be important because some results may be affected by a recent intake of meals or medicines. Variables such as age, gender, ethnicity, time of day (diurnal rhythms), season, tobacco use, or the presence of comorbid conditions may alter analyte levels and must be borne in mind by the interpreting physician. Alterations in renal function may be particularly problematic for the collection of urine specimens. Liver disease or inflammation may alter the levels of acute-phase and metallothionein proteins that bind to nutrient elements and metals.29 Renal wasting disorders may increase urine levels and decrease blood levels of creatinine, minerals, and other analytes. Renal clearance disorders may decrease urine levels of creatinine, minerals, and other analytes.30 Medications, such as diuretics, may alter renal function and mineral levels; all medications may be reviewed with the patient’s pharmacist before interpreting results. 

METHODOLOGY The analytical method used by a laboratory to assess nutrient elements and other metals must be sensitive, specific, accurate, precise, and timely.12 The detection limit of the methodology is important for the analysis of trace or “ultratrace” microminerals. Spectrometry methodologies, such as inductively coupled plasma-mass spectrometry or inductively coupled plasma-optical emission spectrometry, are considered state of the art. Reputable laboratories are Clinical Laboratory Improvement Amendments (CLIA) certified, use highly trained personnel, and choose to participate in third-party proficiency testing.31 Proficiency testing ensures the reproducibility and reliability of the laboratory’s internal quality control programs (IQCPs) and ensures reliable, reproducible results.32 Some of the quality controls that may be used in each batch of samples processed include the use of reagent blanks, the replication of analyses to ensure precision, and the use of certified reference samples with known amounts of the metals of interest to ensure accuracy, specificity, and sensitivity. Reference values for some minerals have been standardized in the literature; for other elements, laboratories must establish their own reference values. 

MINERALS AND DISEASE Several minerals are required to maintain the necessary functions of life.12,11,33 Minerals may be considered essential if a deficiency (lack) of the mineral results in significant disease or death. Nonessential minerals may affect physiologic function and have health benefits, but they have not yet been proven essential. Macrominerals are required in daily amounts of milligrams to grams; microminerals are required in daily amounts of micrograms to milligrams. Some minerals, such as electrolytes, dissociate into charged ions in the body fluids (electrolytes) and may be important in the maintenance of membrane potentials needed for muscle contractions and nerve conduction. Both macroand microminerals are necessary cofactors in metabolic functions, and either an excess or a deficiency may be detrimental to health. Homeostatic regulation maintains the balance of nutrient elements in the body. Regulation mechanisms may include intestinal assimilation, protein chaperones for blood transportation, storage in body tissues, and excretion mechanisms (Fig. 23.1). Homeostatic mechanisms may be disrupted by genetics, poor diet, substances that block assimilation, toxins that displace minerals or compete for receptor sites on enzymes and cells, diseases of malabsorption, liver disease, or renal disorders. Either over- or undernutrition may be problematic for mineral homeostasis.34 High levels of meat consumption in Western diets may excessively raise iron levels, and consumption of processed foods may result in a dietary deficiency

CHAPTER 23  Population average (mean) Deficiency symptoms

Excess symptoms (toxicity)

Homeostasis Subclinical deficiency

Subclinical excess

Fig. 23.1 The level of a mineral element in a tissue sample is determined by mineral availability and individual variance in assimilation, transport, and cellular uptake capacity.12,37

of multiple minerals.35,36 Inherited mutations that disrupt mineral homeostasis are rare, but important, disruptors of patient health. The most common disorders include the iron-storage disorder hemochromatosis, the copper disorders Wilson disease and Menkes syndrome, the zinc-deficiency disorder acrodermatitis enteropathica, and sulfite oxidase deficiency (lack of molybdenum cofactor). The effects of inherited variation in the general population on mineral status is an important new area of research.37 Levels of various nutrient elements have been associated with disease states and may be considered clinical biomarkers.8 Cirrhosis may lower levels of serum selenium,38 calcium,39 magnesium,40 and zinc.41 Emphysema or certain cancers may increase serum copper levels, and both copper and manganese levels may increase during congestive heart failure, infection, or psychoses.42 Heart tissue levels of selenium, iron, copper, zinc, and phosphorus have been associated with ejection fraction and cardiac index.43 In men infected with human immunodeficiency virus (HIV), helper T-type 4 cells appear closely correlated with serum magnesium concentration.44 Although other associations have been observed between trace minerals and breast cancer,45 gastrointestinal malignancy,46 and malignant ascites,47 there have been null studies for these conditions as well. It is important to remember that observed associations between certain disorders may be variable and based on patient status, ethnicity, or the stage of the disease when studied; both may confound the results of such studies. The ratios between some trace elements have been associated with specific disorders. Levels of magnesium and copper, and their ratios, may be predictive for lower limb ischemia, atherosclerosis obliterans, and risk of aortic aneurysm.48 The relative concentrations of copper, zinc, and selenium in whole blood and thyroid tissue may present in specific patterns for various thyroid disorders and thyroid cancer. Serum copper and copper/zinc ratios were shown to be increased in breast cancer but not in benign breast diseases.49 In another study, serum copper-to-zinc ratios were shown to be of diagnostic and prognostic value in head, face, and neck cancer, with alterations in copper, zinc, and the copper-to-zinc ratio related to the stage of the disease.50 Clinicians specializing in the treatment of certain disorders may wish to review the literature for associations between mineral status and the disorder of interest. 

ESSENTIAL MACROMINERALS Calcium Calcium is the most common cation in the body and the primary component of tooth and bone.51 Normal calcium levels are necessary for muscle contraction, enzyme function, protein stabilization, neuron firing, hormone release,52 and blood coagulation.53 Calcium may also act as a second messenger for some cell-signaling pathways. Calcium

Mineral Status Evaluation

195

reserves in the body are maintained through multiple mechanisms, which include parathyroid hormone, dietary calcium intake, assimilation of calcium from the digestive tract, and renal calcium excretion. Disruption of these calcium homeostasis mechanisms may result in either hypercalcemia or hypocalcemia.54,55 The parathyroid gland monitors the blood calcium level and responds to low calcium concentrations by releasing parathyroid hormone (PTH). PTH increases the level of 1,25-dihydroxyvitamin D (calcitriol) and stimulates bone resorption to increase blood calcium levels. Serum calcium is so closely regulated by the parathyroid gland that its use as an indicator of calcium balance is not reliable when considered in isolation. Calcium is also regulated as it is transported across cell membranes; calcium status affects the function of the endoplasmic reticulum, the mitochondria,56 and the sarcoplasmic reticulum of muscle cells. Measurement of physiologically active ionized calcium may be more useful in the independent evaluation of calcium status. Hypercalcemia is defined as a total serum calcium concentration of greater than 10.4 mg/dL or an ionized serum calcium of greater than 5.2 mg/dL.55,57 Hypercalcemia may occur because of excessive bone resorption (immobilization), hyperparathyroidism, vitamin D toxicity, and the presence of cancer or granulomatous disorders. Hypercalcemia occurs when the kidney’s capacity to excrete calcium is exceeded. Mild hypercalcemia may be asymptomatic. More severe hypercalcemia may result in anorexia, nausea, vomiting, constipation, abdominal pain, fatigue, polyuria, arrhythmia, and hypertension.58 Severe hypercalcemia may progress to symptoms of confusion, delirium, and coma. Hypercalcemia may induce renal insufficiency, nephrogenic diabetes insipidus, kidney stones, or vascular and soft tissue calcifications. Hypocalcemia is defined as a total serum calcium concentration of less than 8.8 mg/dL or an ionized calcium level of less than 4.7 mg/dL with normal plasma proteins.55,59 Hypocalcemia may occur because of hypoparathyroidism or pseudohypoparathyroidism, vitamin D deficiency or dependency, magnesium deficiency, acute pancreatitis, hyperphosphatemia, or renal tubular disease. Renal tubular disease may increase calcium excretion into the urine or decrease the conversion of precursors into active 1,25-dihydroxyvitamin D. During pregnancy, serum calcium and albumin levels may decrease. Medications, such as anticonvulsants, rifampin, furosemide, or bisphosphonates, may contribute to hypocalcemia. Steroid medications may decrease the gastrointestinal absorption of calcium. Hypocalcemia is typically asymptomatic but may present with dry and scaly skin, brittle nails, coarse hair, muscle cramps (legs or back), swelling of the optic nerve (papilledema), and cardiac arrhythmia or neuropsychiatric symptoms such as depression, cognitive decline, or psychosis due to diffuse encephalopathy.58,59 More severe hypocalcemia may progress to neuromuscular irritability (spasms, tetany) and sensory parasthesias. Hypocalcemia may be associated with liver disease, nephrotic syndrome, congestive heart failure, or malnutrition. Calcium may be evaluated in serum, whole blood, urine, or hair samples.54,55 Serum calcium is reported as total calcium (approximately 40% protein-bound and 60% ionized calcium ions). High serum protein (albumin) levels may falsely elevate and low serum protein levels may decrease serum calcium levels. A whole-blood analysis of calcium will assess calcium present in serum, the cell membranes, and intracellularly. Urinary calcium levels will reflect gastrointestinal assimilation, bone turnover, and renal filtration. Up to 300 mg/24 hours may be excreted by subjects on unrestricted diets. Hair calcium may reflect nutritional status, and the hair calcium-to-magnesium ratio has been associated with levels of coronary artery calcification in older subjects.60,61 Hair mineral deposition may also be altered by the presence of comorbid disorders.62 However, hair contamination may occur because of calcium-rich “hard” water or hair products (perms, dyes, bleaches).63

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Primary and Adjunctive Diagnostic Procedures

Calcium (Ca) may be considered in relation to phosphorus (P), and a Ca:P ratio of 1.3:1 has been suggested for the maintenance of bone density.64 Reduced calcium and increased phosphorus intake is common in Western diets and results in a low Ca:P ratio. Food sources of calcium include dairy products, canned fish with bones (e.g., salmon, sardines), green leafy vegetables, nuts, and seeds. Assessment of dietary intake of calcium is confounded by multiple factors that affect absorption, such as the quantity of fiber and other natural chelators in the diet,65 gastric acidity, the ratio of dietary calcium to phosphorus and magnesium, gut transit time, and other factors. 

Chloride Because chloride is a halogen, most do not consider it a mineral, but technically it is classified as such. Chloride is the most common anion in the body and is primarily found in the extracellular blood compartment (serum or plasma).66,67 Chloride, with sodium, potassium, and bicarbonate, regulates water distribution, osmotic pressure, pH, and ion balance in the extracellular compartment of the blood. Chloride is necessary for the production of hydrochloric acid in the stomach and is also essential in cellular pump functions. Chloride levels are regulated by renal excretion into urine, and chloride may also be excreted in sweat. Chloride is typically evaluated as part of an electrolyte (serum elements) panel; levels of chloride (Cl) and sodium (Na) indicate the amount of salt (NaCl) in the blood. Symptoms of an electrolyte imbalance may include chronic vomiting, diarrhea, weakness, or respiratory distress. Chloride and other electrolytes may become imbalanced during episodes of metabolic or respiratory acidosis or alkalosis. Renal disorders may also disrupt electrolyte balances.68 Dehydration, diuretic medications, and high doses of either antacids or baking soda may lower chloride levels. Glucocorticoid or mineralocorticoid medications may alter electrolyte balance and increase urine output.69 Chloride ions are obtained through the diet and normally pass easily through the intestinal barrier. Chloride may be evaluated in serum and urine, and urinary chloride is a necessary component of a full electrolyte assessment or metabolic panel.66,67 Chloride sweat testing may be used in the diagnosis of cystic fibrosis.70 Urine chloride analysis, and often the analysis of urine sodium as well, may be important when considering alkalosis or acidosis or when assessing high or low serum chloride levels. Depending on the patient’s condition, serum and urine chloride levels may differ. Urinary chloride may help determine whether chloride loss is related to salt loss or due to an excess of adrenal hormones (cortisol or aldosterone), which may alter electrolyte excretion. Increased serum chloride (hyperchloremia) may occur because of dehydration, Cushing disease, or kidney disease (renal clearance disorders). Acid–base dysregulation resulting in metabolic acidosis or respiratory alkalosis may also increase serum chloride.71 Low serum chloride (hypochloremia) may occur because of congestive heart failure, chronic vomiting, or Addison disease. Lung diseases, such as emphysema, may result in chronic respiratory acidosis and metabolic alkalosis, lowering serum chloride. Decreased urinary chloride may occur because of Cushing disease, primary aldosteronism, congestive heart failure, gastrointestinal malabsorption, or diarrhea. Increased urinary chloride may occur because of dehydration, Addison disease, high salt intake, or insufficient calorie intake. If both urinary chloride and sodium are elevated in a patient on a salt-restricted diet, the patient may not be diet-compliant. See Chapter 12, Fantus Test, for the use of urinary chloride as a measure of salt consumption. 

Magnesium Magnesium is a cation found primarily in the intracellular (35%–45%) compartment of the blood.55,72,73 Up to 55% of magnesium is found

in bone, and this reservoir may be mobilized for the maintenance of serum levels. Serum magnesium levels may affect nerve conduction, muscle contraction, and cardiovascular functions. Transportation of magnesium across the cell membrane is regulated by dedicated transporters. Magnesium is a cofactor for over 300 intracellular enzymes that participate in energy production, oxidative phosphorylation, glycolysis, cell replication, nucleotide (DNA) metabolism, and protein synthesis. Approximately 80% of a cell’s magnesium is bound to ATP, which helps make the ATP bioactive.74 Hypermagnesemia (serum concentration >2.6 mg/dL) is uncommon without magnesium supplementation (or ingested as laxatives or antacids).75 Other causes may include renal failure, hyperparathyroidism, dehydration, early diabetic acidosis, Addison disease, rhabdomyolysis (muscle breakdown), or a history of familial hypocalciuric hypercalcemia. Increased serum magnesium and copper levels may be seen with seizure disorders. High magnesium concentrations may decrease serum calcium levels. Medications that may increase magnesium levels include aspirin, thyroid medication, potassium-sparing diuretics, lithium carbonate, and antibiotics (review medications with a pharmacist).74 Magnesium intoxication may occur if magnesium is supplemented and renal failure is present. Deep tendon reflexes are lost as magnesium levels increase above 5 mg/dL. As levels rise higher, magnesium depresses the nervous system; symptoms of magnesium intoxication may include hyporeflexia, hypotension, lethargy, disorientation, respiratory depression, and cardiac arrhythmia leading to cardiac arrest (>15 mg/dL). Hypomagnesemia occurs because of inadequate magnesium intake, malabsorption, or increased excretion from the kidney or gastrointestinal tract.76 Low magnesium concentrations may be associated with poor diet, alcoholism, inflammatory bowel disorders, poorly controlled diabetes, chronic diarrhea, recent hospitalization or surgery, or toxemia of pregnancy.77 Magnesium blood levels are also lower in the second and third trimesters of a normal pregnancy. Medications such as proton-pump inhibitors, antacids, diuretics, digoxin, insulin, laxatives, phenytoin, glucocorticoids, steroid hormones, hormone antagonists, some antibiotics, antihistamines, and antivirals may decrease magnesium levels (review medications with a pharmacist).74 High doses of calcium, vitamin D, or caffeine may further exacerbate magnesium losses. Low magnesium concentrations may result in symptoms of neuromuscular excitability (muscle cramps, spasms) or cardiac arrhythmia. Good dietary sources include green leafy vegetables, nuts, soybeans, and cocoa mass. Hard water may contain magnesium salts and contribute to magnesium intake. Serum magnesium may be the most commonly used but least accurate assessment of magnesium status.55 The serum magnesium concentration may be influenced by recent dietary intake and other factors; it constitutes only about 1% to 3% of total body magnesium and does not reflect magnesium levels in cells.77 The binding of magnesium to serum proteins is subject to many uncontrollable variables. Serum magnesium levels as low as 1.2 mEq/L have been measured in patients with normal total body magnesium.78 Measurement of magnesium status presents some difficulties; currently, the magnesium retention (load or tolerance) test may be the most accurate, although cumbersome, method of assessment in adults.79 The retention test requires a parenteral infusion of magnesium with subsequent urine collection to evaluate urinary magnesium.80 Other methods of assessing magnesium include ionized magnesium concentrations (in blood, plasma, or serum), urinary magnesium, and erythrocyte concentrations.55 Erythrocyte concentrations of magnesium are not subject to the same transient fluctuations as serum and may be more reliable indicators of status than serum levels.81 The analysis of white blood cell (WBC) magnesium content has also been

CHAPTER 23  explored. The concentration of magnesium in leukocytes has been inversely associated with the risk of tachyarrhythmias. WBC assessments of magnesium may not be accurate in all patients; inherited variation in the MAGT1 magnesium transporter gene82 may reduce the amount of magnesium in WBCs and result in a form of immunodeficiency. The best test to evaluate total body magnesium sufficiency may well be whole-blood analysis because this will assess total magnesium in serum, intracellularly, and in the cell membranes of both red blood cells (RBCs) and WBCs. Ionized magnesium and total magnesium appear to provide similar information.83 Increased urinary excretion in individuals with type 1 diabetes has been shown to decrease erythrocyte levels, without significant hypomagnesemia.84 A 24-hour urinary magnesium may be useful to reflect dietary changes in magnesium intake.85 Healthy kidneys restrict the excretion of magnesium when concentrations or intakes are low and permit excretion when serum levels are restored. The current scientific literature remains divided in regard to hair Mg levels reflecting intracellular levels. External Mg contamination of hair may result from recent hair treatment, hair color, or hard water exposure, confounding hair element evaluations. 

Phosphorus The element phosphorus is a necessary component in cell membranes, DNA, and RNA.55,86 Phosphorus is primarily used in bone mineralization (85%), adenosine triphosphate (ATP) metabolism, pH homeostasis, and cell signaling. Phosphorus is bound to oxygen in all living systems and is found in the body as phosphate (PO43–). Phosphorus, in the form of phosphoryl groups (PO3), is attached to and removed from molecules during cell signaling. Phosphorus homeostasis is regulated by the parathyroid gland and vitamin D. Hyperphosphatemia may occur because of renal insufficiency (GFR < 30 mL/min), hypoparathyroidism, pseudohypoparathyroidism (hormone resistance), or granulomatous disease (immunodeficiency).86,87 Less commonly, hyperphosphatemia may occur because of diabetic ketoacidosis, rhabdomyolysis, tumor lysis syndrome (cancer therapy), and excessive exercise or occasionally because of the excessive use of oral or rectal (enema) phosphate salts. The condition is asymptomatic but may present with symptoms if hypocalcemia is also present (dry and scaly skin, brittle nails, coarse hair, muscle cramps [legs or back], swelling of the optic nerve [papilledema], cardiac arrhythmia, or neuropsychiatric symptoms). Elevated serum phosphate has been associated with an increased risk of cardiovascular disease, heart failure, and kidney disease. Chronic hyperphosphatemia may induce the precipitation of calcium into vascular and soft tissues; the calcifications may appear on imaging studies. The kidney normally compensates for low phosphorus intake. Hypophosphatemia occurs when serum phosphate is less than 2.5 mg/ dL.86,88 Symptoms of hypophosphatemia may include anorexia, anemia, muscle weakness, bone pain, increased susceptibility to infections, peripheral parasthesias, loss of coordination, or respiratory distress. In children, chronic hypophosphatemia may present as rickets; in adults, it may present as osteomalacia. Causes of hypophosphatemia include alcoholism, respiratory alkalosis, the recovery phase of diabetic ketoacidosis, hyperparathyroidism, Cushing syndrome, hypothyroidism, vitamin D deficiency, malabsorption syndromes, renal wasting, severe anorexia nervosa, or the presence of other electrolyte imbalances (hypomagnesemia or hypokalemia). The excessive use of theophylline (respiratory inhalers) or antacids and the chronic use of diuretic medications may also deplete phosphate levels. Phosphate is measured in serum, plasma, or urine.55 Serum or plasma phosphate results may be compromised if specimens are hemolyzed, have a high fat content, or have high bilirubin concentrations. With normal renal function, urinary phosphorus reflects dietary

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status. Hair phosphorus has not been documented to reflect dietary status or biochemical phosphorus status. 

Potassium Potassium is the primary intracellular cation.89–91 Intracellular potassium concentrations may be 30 times higher than serum or plasma levels. The high intracellular levels are maintained by adenosine triphosphate (ATP)dependent cell membrane transporters, which exchange sodium for potassium. The sodium–potassium “pumps” are essential for the maintenance of the ionic gradients (membrane potentials) needed for muscle contractions and nerve conduction. Potassium diffuses out of cells with the concentration gradient if the pump’s activity is inhibited. The kidney is slow to adapt to changes in potassium concentrations in the blood. Hyperkalemia is defined as a serum potassium concentration of greater than 5.5 mEq/L.89,90,92 Symptoms of hyperkalemia may include peripheral tingling or paresthesias; muscle weakness, which rarely progresses to flaccid paralysis; and cardiac arrhythmia, which may progress to ventricular fibrillation or asystole. Hyperkalemia may be asymptomatic until arrhythmias occur. The causes may include increased potassium intake (supplements), kidney injury or chronic renal disease that decrease excretion, hypoaldosteronism, Addison disease (with sodium depletion), congenital adrenal hyperplasia (salt wasting), metabolic acidosis, and dehydration. The ingestion of large amounts of fruit or fruit juices may increase potassium levels. Medications that may contribute to hyperkalemia include potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), heparin, digitalis, α- and β-blocker antihypertensives, and angiotensin receptor blockers. “Pseudohyperkalemia” may occur if comorbid platelet, erythrocyte, or mixed-type blood disorders are present and may result in preanalytical platelet activation or hemolysis.93 It can also occur from excessive, long-term consumption of glycyrrhizin from licorice root. Plasma potassium may be more accurate in such patients. Hypokalemia is defined as a serum potassium concentration of less than 3.5 mEq/L.89,90,94 Hypokalemia may be most apparent in erythrocytes; potassium is primarily an intracellular electrolyte.95 Symptoms of potassium loss may begin with fatigue or muscle weakness and cramping and progress to tetany, rhabdomyolysis (muscle breakdown), respiratory distress, muscle and intestinal paralysis (bloating, constipation, pain), and cardiac arrhythmias. Chronic hypokalemia may impair the kidney’s ability to concentrate urine and result in polyuria (excessive urination) and polydipsia (excessive thirst). Hypokalemia is usually caused by decreased potassium intake or increased potassium losses from the gastrointestinal tract or the kidney. Gastrointestinal losses may be precipitated by severe or chronic vomiting or diarrhea, laxative abuse, bowel diversion surgery, villous adenoma of the colon (rare), or the ingestion of bentonite clay (binds potassium). Renal losses may occur because of Cushing syndrome, hyperaldosteronism, congenital renal hyperplasia, acquired renal tubular dysfunction, or inherited renal-wasting disorders (Bartter, Gitelman, Liddle, or Fanconi syndrome). Hypomagnesemia may induce increased renal excretion of potassium, as may excessive intake of glycyrrhizin, a component of black licorice candies and licorice root herbal supplements. A potassium shift from the intracellular to the extracellular compartment may occur because of hyperthyroidism or the rare, inherited condition familial periodic paralysis. Medications that may contribute to hypokalemia include β-adrenergic agonists, decongestants, bronchodilators, diuretics, mineralocorticoids, glucocorticoids, antibiotics, caffeine, sodium polystyrene sulfonate, and labor-suppressing medications. Fruits, vegetables, seeds, and nuts are good dietary sources of potassium. Potassium supplements may be required by some individuals, but their use must be carefully monitored.

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Potassium concentrations may be evaluated in serum, plasma, erythrocytes, whole blood, or urine.89 Hair potassium has not currently been associated with either dietary intake or nutrient status. Reference values are different for plasma and serum samples. Platelets rupture during coagulation, and the increased potassium is found in the serum, so the serum reference values are higher. The patient’s platelet count may have an effect on the potassium level in serum samples as well; high platelet counts (thrombocythemia, thrombocytosis) may result in pseudohyperkalemia. Blood samples must be processed quickly and correctly to prevent preanalytical errors that may occur. Cooling of a sample before separation may falsely increase serum or plasma potassium levels. Leaving unseparated samples at room temperature for long periods before processing may falsely lower serum or plasma potassium levels. Delayed transport, rough handling, or failure to release the arm tourniquet before blood collection may cause tissue damage and falsely elevate potassium samples as erythrocytes break open. In addition, serum or plasma concentrations may not reflect intracellular losses during early potassium deficiency. The renal tubular response is slow to adapt to potassium depletion and may take a week or more to adjust ion exchanges and conserve potassium. Erythrocyte (RBC) potassium concentrations may be a more accurate indicator of the potassium content in other types of cells than serum or plasma.95 Although RBCs do not have nuclei, the sodium– potassium membrane pump that maintains the proper influx and efflux of these ions is intact and may respond quickly to restore intracellular levels when potassium becomes available. The rapid restoration of intracellular levels is essential for the continued firing of neurons and for cardiac contractility. Reduced intracellular levels have been associated with changes in the cardiac recovery phase (electrocardiograms).96 Evidence indicates that obesity may decrease the efficiency of the sodium–potassium pumps.97 The whole-blood potassium concentration may be almost as accurate as the RBC potassium level because 98% of potassium is intracellular.98 Urinary potassium may be used to confirm and diagnose abnormal blood potassium levels.89 Urinary renal excretion of potassium is also used to estimate daily potassium intakes. A 24-hour collection is the preferred reference method, although collections of shorter duration (7 p.m.–7 a.m.) may also be acceptable.99 Within the reference values, the highest tertile (third) of potassium excretion has been associated with a decreased risk of hypertension,100 cardiovascular events, and mortality.101 Urinary potassium concentrations may decrease because of low aldosterone levels or the use of medications such as NSAIDs, beta blockers, or pharmaceutical lithium. Urinary potassium levels may increase because of renal disease or rhabdomyolysis (muscle breakdown). 

Sodium Sodium is the primary cation in the extracellular fluid.89,102 The sodium–potassium ATPase pumps maintain the intracellular potassium and extracellular sodium concentration gradients and establish the membrane potentials necessary for neuron firing, cardiac function, and muscle contraction. Sodium is evaluated as part of an electrolyte (serum elements) panel; levels of sodium (Na) and chloride (Cl) indicate the amount of salt (NaCl) in the blood.103 Symptoms of an electrolyte imbalance may include chronic vomiting, diarrhea, weakness, or respiratory distress. Electrolytes are commonly monitored in patients with hypertension, heart failure, and liver or kidney disease. Sodium is absorbed by the gastrointestinal system, and the kidneys excrete all but 1 to 2 meEq/L of the approximately 200 meEq/L of sodium chloride ingested daily. Sodium, with chloride, potassium, and bicarbonate, regulates water distribution, osmotic pressure, pH, and ion balance in the extracellular compartment of the blood. Disruption of the body’s

fluid volume or fluid-compartment equilibrium may occur if there is a loss, gain, or inappropriate retention of either sodium or water. The regulation of extracellular water and sodium status occurs in the renal tubules of the kidneys. The extracellular fluid volume includes the blood volume, and signaling systems that regulate blood pressure, including the renin–angiotensin–aldosterone system, antidiuretic hormone, and renal dopamine, may alter sodium and water regulation in the kidney. Hypernatremia is a hyperosmolar condition, defined as serum sodium of greater than 145 mEq/L, and occurs when water loss is greater than water intake.102,104 Hypernatremia is uncommon with normal kidney function but may occur because of dehydration, Cushing syndrome, diabetes insipidus, adrenal tumors (secrete deoxycorticosterone), congenital adrenal hyperplasia, osmotic diarrhea, hypothalamic disorders, or an impaired thirst mechanism.105 Hypernatremia may be more common in the aged, those with impaired mental status, and infants because these individuals may have difficulty rehydrating unassisted. Hypernatremia commonly presents with thirst and proceeds to neurologic symptoms (confusion, agitation, dry mucous membranes, decreased urination, muscle spasms, parasthesias, tremors, ataxia, seizures, coma) as water shifts from cells into the extracellular compartment. Medications such as anabolic steroids, diuretics, glucocorticoids, laxatives, cough medications, and oral contraceptives may increase sodium levels (review medications with a pharmacist). Hypernatremia resulting from salt ingestion rarely occurs with normal renal function. The treatment of hypernatremia depends on the water (fluid) status of the patient. Hypernatremia may be hypovolemic (extracellular water loss greater than sodium loss), euvolemic (increased sodium but normal extracellular water levels), or hypervolemic (sodium levels increase and extracellular water increases). Urine sodium and osmolality may be used with serum assessments to determine whether the kidney is the cause. Hyponatremia is defined as a serum sodium level of less than 136 mEq/L and indicates an excess of extracellular water volume compared with sodium concentration.89,102,106 Low serum sodium levels may be caused by a water–sodium imbalance or by the presence of excess glucose or lipids in the blood (“pseudohyponatremia”). Causes of sodium loss may include diarrhea or vomiting, renal disease or injury, mineralocorticoid deficiency, Addison disease, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion (SIADH), cirrhosis, heart failure, pancreatitis, rhabdomyolysis, physical or emotional distress (increased vasopressin), small bowel obstruction, or increased fluid intake. Endurance or extreme sports athletes may ingest large quantities of water during events and experience acute hyponatremia if they do not replace salt as well. Symptoms of hyponatremia include nausea, weakness, confusion, and lethargy and may progress to ocular palsy, confusion, and coma if the sodium loss becomes severe. Medications that may contribute to hyponatremia include thiazide diuretics, barbiturates, carbamazepine, chlorpropamide, clofibrate, opioids, tolbutamide, ACE inhibitors, tricyclic antidepressants, NSAIDs, and vincristine. Dietary sources primarily include table salt, sea vegetables (e.g., kelp, seaweed), dairy products, and spinach. Hyponatremia may occur during isosmotic, hyperosmotic, or hypoosmotic conditions.89,106,107 Isosmotic hyponatremia is actually pseudohyponatreima; plasma sodium is decreased, but osmolality, glucose, and urea levels are normal. The phenomenon is exclusive to samples assessed using flame emission spectrophotometry or ionselective electrodes and only occurs in samples from patients with hyperproteinemia or severe hyperlipidemia. Hyperosmotic hyponatremia occurs most commonly because of severe hyperglycemia as the water and sodium shift compartments to compensate for the excess glucose. Sodium levels will decrease about 1.6 mEq/L for every 100 mg/ dL increase in glucose.

CHAPTER 23  Hypoosmotic hyponatremia occurs because of a greater loss of sodium (depletional) compared with water or because of an increase in the extracellular water volume (dilutional). Depletional hyponatremia presents clinically with orthostatic hypotension, tachycardia, and decreased skin turgor (“tenting”). Low urine sodium during depletional hyponatremia indicates an appropriate renal response; the loss is likely from the gastrointestinal tract or the skin (excessive sweating). High urine sodium indicates renal wasting of sodium, metabolic alkalosis, or the use of thiazide diuretics. Dilutional hyponatremia occurs because of water retention and presents clinically as weight gain or edema. This may occur because of renal disease or nephrotic syndrome, congestive heart failure, or hepatic cirrhosis. If hypoosmotic hyponatremia presents with normal extracellular water volume, likely causes include SIADH and deliberate excess water intake. Sodium is most commonly measured in blood or urine, although it may also be measured in sweat, feces, and gastrointestinal fluids.89 Whole blood, serum, or heparinized plasma may all be used to assess sodium concentrations, although no information on the status of the extracellular compartment will be available from whole-blood analysis. Urinary sodium is always evaluated as a component of sodium blood level evaluations. Urinary sodium may be increased because of an increased blood sodium level, Addison’s disease, diuretic use, or renal wasting of sodium. Higher urinary sodium levels have been associated with an increased risk of cardiovascular events and mortality.108 Urinary sodium levels may be low because blood levels are low; because urinary excretion of sodium is compromised (nephrotic syndrome); or because of dehydration, congestive heart failure, or liver disease. 

ESSENTIAL MICROMINERALS Copper Copper is an essential component of copper-incorporating oxidase enzymes and other metalloproteins.12,109,110 Copper-dependent enzymes are necessary for energy production (cytochrome c oxidase), collagen cross-linking, hemoglobin synthesis, norepinephrine synthesis, histamine catabolism (diamine oxidase), melanin synthesis, and antioxidant status (superoxide dismutase). Two thirds (about 60 mg) of total body copper is sequestered in bone or muscle tissues. Free copper ions may interact with cellular components to generate free radicals. Special “chaperone” proteins keep intracellular copper bound to prevent this cellular damage by free copper ions; however, inherited variations in chaperone proteins may compromise their ability to bind copper.111 Copper absorbed from the gastrointestinal tract is bound to albumin and transported to the liver. Ninety percent of the copper exported from the liver is bound to ceruloplasmin; urinary excretion is limited to ionic, not bound, copper. Both copper excesses and deficiencies may be inherited or acquired. Inherited conditions are the result of genetic mutations and are usually X-linked (maternal inheritance). Acquired conditions may be the result of environmental exposures or supplementation choices. Excess copper in the body may have toxic effects.12,109,110,112 High levels of intracellular copper may inhibit protein synthesis or gene expression. Copper excess may be acquired or the result of inheritance. True acquired toxicity (poisoning) is rare but may occur because of contamination (storage of acidic foods or beverages in copper containers, contaminated water, or cooking in corroded copper or with brass utensils). Symptoms after ingestion may include nausea, vomiting, and diarrhea. Excess copper is primarily excreted in the bile, and liver disorders that decrease bile excretion may increase copper levels. Subclinical acquired copper excess may require a liver biopsy with visualization of Mallory hyaline bodies for confirmation. Rarely,

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large amounts of copper may be accidentally absorbed through the skin or ingested (gram quantities). Symptoms may then progress to hepatotoxicity, hemolytic anemia, and anuria (renal failure) and may result in death if not promptly treated. High copper levels may be seen with rheumatoid arthritis and some types of cancers. Serum copper and magnesium may be increased with seizure disorders.113 The use of carbamazepine or phenobarbital may increase copper blood levels (review medications with a pharmacist). Individuals with Wilson disease, a genetic disorder of impaired copper transportation, may be at risk for toxic effects at copper intake levels considered normal for the average population and may present with low ceruloplasmin; Kayser– Fleischer rings in the cornea; and hepatic, neurologic, psychiatric, or reproductive disorders.114 Clinical hypocupremia is rarely noted because of dietary deficiency.12,109,110,112 Acquired copper deficiencies may occur because of childhood protein deficiency (kwashiorkor), persistent infant diarrhea (cow’s milk–based diet), malabsorption syndromes, gastric surgery, or excessive zinc supplementation (>50 mg daily). Copper deficiency may delay normal development or result in symptoms of neutropenia, osteopenia, myelopathy, neuropathy, optic neuritis, and iron-resistant hypochromic anemia. Levels of serum copper and ceruloplasmin may, or may not, be low. Copper deficiency may be found in association with premature birth, cystic fibrosis, or aceruloplasminemia (iron deposition). Menkes syndrome is an X-linked mutation in males that results in low ceruloplasmin and low copper levels in serum, the liver, and copper-dependent proteins. Severe symptoms (intellectual disability, gastrointestinal symptoms, hypopigmentation, skeletal changes, hair texture changes, arterial ruptures) occur in affected individuals, and the diagnosis is usually made in early childhood. Individuals with less severe disease may have partial enzyme activity and a milder form of the disease (occipital horn syndrome). Subcutaneous injections may restore peripheral copper levels, but passage through the blood–brain barrier remains limited. Dietary copper sources include beans, eggs, fish, fresh fruits, liver, milk, mushrooms, nuts, oysters, peas, poultry, and whole grains. Copper may be evaluated in serum, plasma, whole blood, erythrocytes, urine, stool, and hair.11,12 Hair may provide an estimate of nutritional copper status, and hair copper levels may increase or decrease in certain disease states.115–117 However, hair cannot discern the presence or absence of inherited copper metabolic disorders, and hair may be easily contaminated by copper-based products used in pools, hot tubs, or plumbing. Fecal copper levels reflect excess dietary copper from bile excretion and unassimilated dietary copper in the stool. Urinary copper reflects the excretion of ionic copper and may be used in conjunction with blood levels to assess the presence of inherited copper metabolic disorders. Accurate urinary copper assessments require normal renal function. Urinary copper may be very high if patients with Wilson disease are treated with chelators during urine collection. Wilson disease is diagnosed when serum ceruloplasmin is low but urinary copper excretion is high.114 Menkes disease is likely if blood, urine, and hepatic copper levels are low. The most frequently used assessments of copper status are serum or plasma copper and ceruloplasmin.11 If excess copper intake or exposure is suspected, then whole blood (total copper) and ceruloplasmin may be the best choice because the sample includes both intracellular and extracellular copper. Erythrocyte copper may have some utility in certain patient populations, such as patients with Alzheimer’s disease, where elevated RBC copper has been found in Alzheimer’s subjects but not in controls.118 

Iodine The element iodine, ingested as the compound iodide, is essential for the synthesis of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).19,119 Metabolic activity (ATP production, protein

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synthesis, enzyme activity, development of skeleton and nervous system, etc.) is regulated by thyroid activity. Thyroid function is regulated by thyroid-stimulating hormone (TSH) from the pituitary gland, which increases the uptake of iodine by the gland. Approximately 80 μg of iodine is used to synthesize thyroid hormones daily. A healthy thyroid gland concentrates about 75% of total body iodine (15–20 mg). Iodide intake varies based on location and the amount of iodide available in the soil. Landlocked populations and those at higher altitudes, far from the ocean, may be more at risk of iodine deficiency. The accumulation of radioactive iodine (131I) in the body may occur after accidental emissions from nuclear power plants and increase the risk of developing thyroid cancer; the uptake of 131I is less likely with adequate iodine status. Iodine excess may occur if doses of greater than 1.1 mg daily are chronically ingested by iodine-sufficient adults.120,121 Exceeding this dose may increase the risk of iodine-induced dysfunction in susceptible populations, such as individuals with iodine deficiency, preexisting thyroid disease, the elderly, neonates, or during pregnancy (prenatal exposure). Although there are biological mechanisms in place to control thyroid hormone synthesis during iodine excess,122 the iodine exposure may also increase TSH and the risk of goiter and hypothyroidism in some susceptible individuals and in neonates.123 Excess iodine may also increase the risk of thyroiditis and thyroid papillary cancer. The accidental ingestion of more than 50 mg of iodine daily for 2 months by 43 older adults occurred during a study, and the effects were reviewed in a separate study.124 Of the 43 subjects taking the high iodide dose, 10 subjects developed hypothyroidism (elevated TSH) while taking the iodide; all but two had returned to normal TSH levels 1 month after discontinuing the iodide supplement. Three subjects developed hyperthyroidism (low TSH) while taking the iodide dose, which persisted 1 month after discontinuation. High levels of iodine exposure may occur if iodinated radiographic contrasts or medications such as amiodarone are used (review medications with pharmacist). Iodine excess may result in symptoms of increased salivation, gastrointestinal irritation, acne-like skin lesions, and a brassy taste in the mouth. Acute iodine poisoning may include symptoms of a burning feeling in the mouth, throat, and stomach; fever; nausea, vomiting, and diarrhea; weak pulse; and cyanosis. Symptoms may progress to coma. High doses of iodine may be contraindicated with antithyroid medications, ACE inhibitors, and potassium-sparing diuretics and during pregnancy. Large doses of potassium iodide may decrease the efficacy of the anticoagulant coumarin. Iodine deficiency may result in various disorders.119–121 If iodine intake is less than 100 μg per day, TSH levels will rise. During deficiency, the thyroid gland is stimulated by increasing levels of TSH and increases in size because of overstimulation by TSH (colloid goiter). Most individuals remain euthyroid, but if iodine deficiency is severe, hypothyroidism may result. Iodine deficiency in adults may impair cognitive function and is the most common cause of goitrous hypothyroidism. Perinatal iodine restriction may have permanent developmental effects on cognition and may result in lower IQ levels. During pregnancy, iodine requirements roughly double. Maternal deficiency may increase the risk of attention deficit and hyperactivity. Severe maternal deficiency (development of goiter) causes cretinism (cognitive impairment, deafness, motor impairments, poor growth, developmental delay), miscarriage, or stillbirth. Food sources of iodine include sea vegetables, seafood, dairy, eggs, and grains; all food sources are highly variable in iodine content due to local conditions and production practices. Dietary iodide is easily assimilated by the gastrointestinal tract, but consumption of goitrogenic (soy, cassava, cruciferous vegetables, some beans, millet, and sweet potato varieties) foods may prevent uptake. Iodized table salt may be an acceptable source

of iodide; however, restaurants and processed food manufacturers rarely use iodized salt in food production. Adequate selenium, iron, and vitamin A are required to support iodine use by the thyroid gland. Tobacco use may impair iodine uptake by the thyroid gland. The presence of intestinal parasites, such as Ascaris lumbricoides, hookworm, or Entamoeba histolytica, may prevent iodide absorption by the gastrointestinal tract.125 Many environmental toxins, especially metals, impair iodine absorption and utilization (see Chapter 183, Hypothyroidism). Urinary iodine is the international standard for the evaluation of iodine status because more than 90% of dietary iodine is excreted in the urine within 24 to 48 hours of ingestion.11 Although often used as a surrogate,126 the assessment of serum thyroid biomarkers has limited utility in the evaluation of iodine status.127,128 Whereas some studies show no association between TSH, T4, and urine iodine levels, other studies indicate that serum T4 may be a conditionally useful biomarker in children and adults. Interventional studies indicate that serum TSH levels may be reflective of iodine status in newborns but are not a sensitive indicator of iodine status in developing children or adults, although serum thyroglobulin may be used in school-aged children. Similar studies indicate that serum TSH may be a useful indicator of iodine status in pregnant or nursing women. Serum T4 is not considered accurate for pregnant or nursing women. For serum T4 to be an accurate surrogate for iodine, there must be a moderate baseline T4 status. Iodine intake over the past few days is best reflected in urinary iodine assessments. The World Health Organization defines iodine deficiency as median urinary iodine concentrations of less than 100 μg/L (< 150 μg/L during pregnancy).126 Urinary iodine excretion of greater than 300 μg (> 500 μg during pregnancy) is considered excessive. Urinary iodine of less than 20 μg/L is considered severe deficiency. Multiple 24-hour urine collections are recommended to estimate iodine intake in individual subjects. It has been suggested, in a non– peer-reviewed trade magazine, that whole-body sufficiency of iodine may be assessed in urine using an “iodine loading test.” The interpretation of the results of this test presupposes specific receptor/storage sites that take up and store iodine/iodide.129 When body storage of iodine/ iodide is optimal, the percentage excretion of an oral loading dose of iodine/iodide excreted in urine is maximal; some authors purport that body stores are optimal when excretion is 90% or more. 

Iron Iron is distributed into virtually all compartments in the body.130 Iron is used by peroxidase, cytochrome, and other enzymes, such as cystathionine-β-synthase (CBS) and enzymes of the tricarboxylic acid cycle. Iron is found in nonenyzme proteins such as hemoglobin, myoglobin, and mitochondrial iron–sulfur clusters131; storage proteins such as ferritin or hemosiderin; and in the transport protein apo-transferrin. Strict conservation of iron stores in the body, even when iron is in excess, results in the loss of approximately only 1% of total body iron daily. Regulation of iron intake occurs in the gastrointestinal tract, where iron assimilation may be modulated by hepcidin so that about 1 milligram of iron is absorbed daily.132 Both iron excess (overload) and iron deficiency may impair homeostasis133; the abnormal distribution of iron during various disease processes may contribute to their symptomology and presentation. Iron overload may be acquired or hereditary.132,134 Acquired iron overload (hemosiderosis) may occur because of excessive iron therapy, hemodialysis, multiple blood transfusions (for sideroblastic anemia, hemolytic anemia, pyruvate kinase deficiency, and thalassemia major), acute overdose, chronic liver disease, or alcoholism. Individuals with β-thalassemia intermedia may develop iron overload because of increased intestinal absorption. An acute iron overdose damages organs and intestines, resulting in vomiting and diarrhea.

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TABLE 23.1  Anemia of Inflammatory Responsea,130,141,143 Disorder

Serum Iron

TIBC

UIBC

Transferrin

Transferrin % saturation

Ferritin

Hemoglobin

Iron deficiency B12 deficiency Anemia of chronic disease Hemochromatosis Thalassemia Porphyria cutanea tarda

Low High Normal or Low

High Low Normal or Low

Low High Normal or High

High Low Normal or Low

Low High Normal or Low

Low High Normal or High

Low Low Low

High High High

Low Low Low

High High High

Low Low Low

High High High

High High High

Normal Low Normal

TIBC, Total iron-binding capacity; UIBC, unsaturated iron-binding capacity aAdapted from the Iron Disorders Institute. http://www.irondisorders.org. Accessed November 1, 2017.

Hereditary hemochromatosis occurs primarily in Caucasians of Northern European descent and is the result of mutations in the HFE gene. The disease is characterized by iron accumulation in the liver and other organs (C282Y homozygous or C282Y heterozygous together with a heterozygous H63D or S55C).135 Early symptoms include fatigue and lethargy; characteristic late symptoms include bronzing of the skin (palms), cirrhosis, diabetes, and increased risk of hepatocellular carcinoma and neurodegenerative diseases.132,133,136 Juvenile hereditary hemochromatosis, from mutations in the HEF2 or HAMP genes, results in symptoms that present before 30 years of age and that include hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis.137 Other mutations result in African iron overload (also known as Bantu siderosis) and ferroprotein deficiency, iron-storage diseases that deposit iron primarily into macrophages. Inherited disorders such as aceruloplasminemia, hypotransferrinemia, Friedreich ataxia, and porphyria cutanea tarda may also result in iron overload. Iron deficiency is one of the most common mineral deficiencies worldwide,130,132,134 although isolated iron deficiency is uncommon in the United States.133 Iron deficiency is most common in children, reproductive-aged women, and the elderly. Deficiency may be secondary to poor diet, obesity, chronic kidney disease, gastrointestinal malabsorption, gastrointestinal tumors,138 gastrointestinal parasites, gastric bypass surgery, or blood loss. Blood losses may result from comorbid disease, blood donations, or extreme endurance training. Iron depletion occurs in gradual stages, and different biomarkers are useful at different stages. Iron-deficiency anemia may result in symptoms such as fatigue, pallor, headaches, dizziness, impaired cognitive function, behavior or motor difficulties (developing children), poor immune responses, decline in exercise performance, tachycardia, dyspnea, and difficulty regulating temperature (iodine deficiency or comorbid hypothyroidism). Symptoms may progress to nail spooning, brittle nails, loss of taste, angular cheilosis (skin lesions at the corners of the mouth), atrophic glossitis (“bald,” sore, tongue),139 or pica. Co-occurring deficiencies in vitamin A, copper, or zinc may further impair iron metabolism. Dietary sources include beans, dark green leafy vegetables, dates and figs, dried fruits, egg yolk, fish, molasses, nuts, organ meats, red meat, shellfish, and whole and enriched grains. Iron deficiency may increase manganese absorption by the gastrointestinal tract. A variety of tests and methods may be used to assess iron status,130,132,134 and a variety of physiologic conditions must be considered when interpreting iron results (see Table 23.1).130,140 Serum iron, total iron-binding capacity (TIBC), serum transferrin, serum ferritin, hematocrit, hemoglobin, soluble transferrin receptor, and zinc protoporphyrin may all play a role in diagnosing iron disorders. The use of various commercial methodologies to measure some of these analytes requires each

laboratory to establish its own reference values for those tests. Although the majority of iron is sequestered inside the erythrocytes as heme iron, and iron supplementation improves RBC hemoglobin content (during pregnancy), erythrocyte iron is not commonly measured in conventional laboratories.142 Iron test results may be affected by diurnal variation (test in morning), stage of menstrual cycle, use of iron supplements or intake of a high-iron diet, oral contraceptives (raise iron values), hepatitis, and the presence of acute or chronic inflammation. Methotrexate may increase iron test results. Testosterone, high-dose aspirin, metformin, and adrenocorticotropic hormone may decrease iron test results. Serum iron evaluates the level of iron in circulation.140 A low serum iron with a high transferrin or TIBC may be an indication of iron deficiency.130,143 During chronic diseases, serum iron, transferrin, and TIBC are all decreased. Serum iron increases, and unsaturated iron-binding capacity decreases during iron overload. High levels of stress or sleep deprivation may transiently decrease serum iron levels. TIBC is assessed by saturating a blood sample with iron and comparing the saturated sample (transferrin saturation) with the serum iron results to obtain the TIBC and the transferrin percent saturation: Transferrin % saturation =

serum × 100 TIBC

Normally, about 30% of transferrin is bound to iron. Transferrin levels will decrease because of liver disease, nephrotic syndrome, low protein intake, or iron overload, and the transferrin saturation will increase. TIBC levels will increase during iron deficiency, and the transferrin saturation will decrease. Plasma iron levels decline in stage 2 iron deficiency, and TIBC rises. Serum transferrin represents the unsaturated iron-binding capacity (UIBC) and may be used instead of the more expensive transferrin saturation test: TIBC = UIBC + serum iron

Transferrin levels may decrease because of nephrotic syndrome or other renal-wasting disorders.144 Hemoglobin levels usually remain in range during stage 2 iron deficiency, whereas serum transferrin receptor concentrations increase. Ferritin is the primary intracellular iron-storage protein, and serum ferritin estimates the amount of iron stored in the body.130 Serum ferritin decreases during the first stage of iron deficiency as iron stores are depleted and bone marrow iron decreases. Low levels of ferritin indicate iron deficiency; however, high levels may occur not only with iron-storage disorders but with a variety of acute and chronic diseases or with the presence of malignancy. Hemoglobin is found within erythrocytes, and the hematocrit value roughly estimates the number of RBCs.144 Hemoglobin and

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hematocrit values are assessed during a complete blood count. In the third stage, iron-deficiency anemia (IDA), hemoglobin and hematocrit levels decrease, and microcytic hypochromic anemia occurs. An elevated hematocrit may indicate polycythemia, dehydration, pulmonary disease, congenital heart disease, renal tumor, tobacco use, or highaltitude living. Hematocrit results may also be altered by recent blood transfusion or donation. The soluble transferrin receptor (sTfR) is used when ferritin results may be compromised by a preexisting or concurrent inflammatory disorder (ferritin is an acute-phase reactant during inflammation).145,146 The sTfR assessment is not affected by the level of inflammation and may be used to discern whether anemia is caused by iron deficiency or chronic disease. sTfR rises with the onset of iron-deficient erythropoiesis and continues to rise as iron deficiency progresses to anemia. sTfR will also elevate because of hemolytic anemias, myelodysplastic syndromes, and the use of erythropoietic stimulation medications. Importantly, sTfR does not rise during anemia of chronic disease. Zinc protoporphyrin (ZPP) is a heme-precursor protein.147 When there is insufficient iron to synthesize heme, or if an exposure to the toxic element lead occurs, ZPP levels rise. ZPP is measured in the free erythrocyte protoporphyrin test, and a ZPP:heme ratio may be included in the results. A change in the ZPP:heme ratio may be the first indication of insufficient iron reserves in pediatric populations, and the ratio will shift before symptoms of iron deficiency appear. ZPP may also be elevated due to comorbid infection, inflammatory disorders, anemia of chronic disease, or inherited porphyria. The results must be interpreted with the patient’s symptoms and history in mind. Iron levels may occasionally be evaluated in urine or hair. Urinary iron excretion is variable and is not considered to reflect tissue iron stores; however, increased urinary iron excretion may be an indicator of exposure to the toxic element lead.148 Increased iron excretion may be a causative factor in intractable IDA and may be evaluated in such cases.149 The iron levels in hair have not been correlated with more conventional blood estimates of iron status; however, research continues in this area. Recent studies have correlated low hair iron (and other elements) with growth retardation62 and demonstrated a positive association between hair iron levels and levels of behavioral traits (novelty seeking, extraversion) and physical activity.150 

Manganese Manganese is an essential cofactor for enzymes in multiple biochemical pathways, including antioxidant protection (mitochondrial superoxide dismutase), glucose synthesis (pyruvate carboxylase), the urea cycle (arginase), and connective tissue and cartilage synthesis (glycosyltransferases).12,151 Although essential, manganese at high levels may have toxic effects in the nervous system. Manganese and iron may compete for uptake in the gastrointestinal system. Manganese uptake increases during iron deficiency and decreases during a high-iron meal. Manganese is transported in the body bound to albumin or transferrin and excreted from the body primarily through the bile. Manganese levels of greater than 5.4 μg/L serum or greater than 20 μg/L whole blood indicate manganese exposure or retention.12,152 High levels of manganese exposure may occur because of occupational inhalation of manganese dust; inhalation of methylcyclopentadienyl manganese tricarbonyl (MMT) gasoline additive; or ingestion of manganese in supplements, food, or water.151 Exposed infants and children may not excrete manganese efficiently until their hepatic systems are fully developed, and adults with liver disease may have cholestasis and increased manganese retention. Symptoms of hypermanganesemia may contribute to hepatic encephalitis and resemble the neurologic symptoms of Wilson disease or Parkinson’s disease; however, manganism is unresponsive to L-dopa therapy.152–154 In rare individuals, a

mutation in the SLC30A10 zinc/manganese cellular transporter may result in a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia,155 which may run in families. Human manganese deficiency has been demonstrated in small experiments or during chronic parenteral nutrition.12,151,152 Symptoms in children may include growth delays and skeletal abnormalities. Symptoms in adults may include low cholesterol; skin rash or lesions; abnormal glucose tolerance; and increased blood calcium, phosphorus, and alkaline phosphatase. Human studies indicate that low manganese levels may increase the risk of seizures156 and may be associated with Alzheimer’s disease and risk of cognitive impairment.157 Dietary sources include dark green leafy vegetables, dried fruits, dried legumes, nuts, and whole grains. Manganese levels may be assessed in serum, whole blood, erythrocytes, urine, and hair.12,13,158,159 For serum collections, a plastic cannula should be used to prevent contamination from steel needles, and specimens should be discarded and redrawn if hemolysis occurs during sample collection or processing. Serum manganese levels represent approximately 30% of total body manganese and may vary based on recent dietary intake. Serum manganese may also require an evaluation of lymphocyte manganese superoxide dismutase activity to accurately assess nutritional deficiency. Whole-blood levels may be used to monitor manganese excess and may provide a more accurate assessment of recent dietary intake over the life span of the RBC (60–120 days).160 Erythrocyte manganese represents about 60% of total manganese and may provide further diagnostic insight for specific conditions such as prolidase deficiency (imidodipeptiduria),161 which presents with increased erythrocyte manganese and normal serum levels. Urinary manganese is considered to have a short half-life postexposure and may better reflect recent dietary and environmental exposures rather than body nutritional status. Hair manganese has been evaluated in multiple studies,162–164 but the possibility of external contamination must be eliminated before the interpretation of results.165 

Molybdenum Molybdenum is an essential cofactor for enzymes involved in sulfur metabolism (e.g., sulfite oxidase), uric acid synthesis (xanthine oxidase), and detoxification (aldehyde oxidase, mitochondrial amidoxime reducing component).12,166,167 The element must be complexed into a pterin protein to act as a cofactor in biochemical reactions,168 and inherited deficiency of the cofactor results in microcephaly, developmental delay, and neurologic symptoms within a week of birth. Affected individuals have increased levels of urinary sulfite, S-sulfocysteine, xanthine, and hypoxanthine and decreased uric acid in their blood.169 Molybdenum is assimilated in the gastrointestinal tract as molybdate (MoO2-4); once assimilated, more than 80% of the molybdate binds to erythrocyte proteins. Excess dietary molybdenum is excreted by the kidneys, and experimental ingestion of up to 1.5 mg daily for 24 days produced no adverse effects in young men.170 Dietary molybdenum excess in humans is not well documented. Ingestion of 10 to 15 mg of molybdenum in the daily diet occurs in some isolated Armenian populations and has been correlated with increased blood levels of uric acid. Increased uric acid, arthralgias, and ceruloplasmin levels have been reported with occupational molybdenum exposures.12 Reported dietary deficiency is rare but has been documented when molybdenum-deficient parental nutrition has been administered to patients. Chronic molybdenum deficiency causes sulfite toxicity.171 Deficiency symptoms included tachycardia, tachypnea, headache, nausea, vomiting, and progression to coma. Animal studies indicate that tungsten exposures may increase the excretion of molybdenum, even when molybdenum is deficient in the diet.172 Dietary sources of molybdenum include beans, peas, red meats, and whole grains.

CHAPTER 23  Molybdenum was once considered difficult to measure, but inductively coupled plasma mass spectrometry has sufficient sensitivity to measure molybdenum in biological samples, such as whole blood, erythrocytes, serum, plasma, or urine.12 The average value for whole blood is 1 μg/L; for plasma or serum, the average is 0.5 μg/L. Urinary molybdenum ranges, on average, from 40 to 60 μg/L daily and varies with dietary intakes. Urinary molybdenum has been compared with femoral neck and lumbar bone mineral densities, and an inverse relationship has been found: the higher the urinary molybdenum, the lower the bone mineral density.173 

Selenium Selenium is an essential component of selenoproteins vital for various metabolic and antioxidant functions.12,174,175 Selenoproteins all contain selenocysteine, which is now considered the 21st amino acid. Glutathione peroxidase (antioxidant), iodothyronine deiodinase (thyroid hormone), thioredoxin reductase (intracellular redox status), and selenophosphate synthase (selenoprotein synthesis) all require selenocysteine in their structures, as do the antioxidants selenoprotein P and selenoprotein W. The human synthesis pathway has only recently been defined and may be affected by inherited variations in the pathway enzymes,176 with clinically significant results. Animal studies indicate that selenium may have synergistic antioxidant effects with vitamin E.177 Dietary selenium is primarily selenomethionine. Both organic and inorganic selenium may be absorbed by the gastrointestinal system, although the absorption of some inorganic selenium may require the presence of glutathione.178 Intakes in the United States and Canada are generally considered sufficient. Selenium sufficiency may reflect dependence on local food production; in some areas of the world, selenium-deficient soils and dependence on locally grown foods may predispose human populations to selenium deficiency; in other areas, high selenium levels may be found. Excess selenium is normally excreted by the kidneys. Toxic levels of selenium exposure may occur because of supplementation, industrial exposure, or high levels in local soil or water, which may bioaccumulate into food plants and animals.12,174,175 Chronic exposure to high amounts of selenium in food, water, or soil may increase the risk of amyotrophic lateral sclerosis.179 Inorganic selenates may be more toxic than organic selenium compounds and may cause symptoms at lower levels of exposure.180 Early signs and symptoms of selenosis (chronic exposure) include a “garlic” odor on the breath, brittle nails, and hair loss and progress to fatigue, irritability, gastrointestinal symptoms, mottled teeth, skin rashes, and neurologic disorders. Toxic effects have been associated with selenium intakes of 850 μg daily. The tolerable upper intake level for adults is 400 μg daily from all sources, but newer evidence indicates that daily intake in excess of 250 to 300 μg daily may increase the risk for type 2 diabetes, dermatitis, and hair loss. Selenium deficiency may occur because of low levels in local soil and water, because of malabsorption syndromes, or because of inherited variations in selenocysteine insertion protein (SECISBP2 tRNA), which impairs thyroid hormone synthesis and antioxidant status and decreases plasma selenium levels.176 Systemic selenoprotein deficiency results in photosensitivity and hearing loss; the effects of partially active pathways are unknown at present. Symptoms of severe deficiency may include muscle weakness, muscle wasting, and cardiomyopathy. Severe deficiency may also decrease male fertility.12,174,175 Severe dietary selenium deficiency during child development may result in multifactorial Keshan (cardiomyopathy) or Kashin–Beck (joint deformities, dwarfism) disease; these conditions are seen primarily in areas of China with selenium-deficient soil. The

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risk of deficiency may be increased because of bariatric surgery, malabsorption syndromes, renal dialysis, and specialized medical diets (phenylketonuria, homocystinuria, maple syrup urine disease). Selenium levels may be lower in HIV+ individuals in developing countries or due to local selenium-deficient soils. Marginal selenium deficiency may impair cognitive function,181 thyroid function, and immune or inflammatory responses. Deficiency may increase the risk of cardiovascular disease, reproductive disorders, or mood disorders. Poor immune responses in selenium-deficient individuals may increase viral virulence and the severity of viral diseases. The use of cisplatin or other medications may decrease selenium levels (review all medications with a pharmacist). Dietary sources of selenium include Brazil nuts,182 fish, seafood, meat, brown rice, and sunflower seeds. Selenium status may be evaluated by whole blood, serum, plasma, urine, and hair.12 The types of selenium ingested may sequester in different compartments in the blood; organic selenium increases plasma and urine levels, whereas inorganic selenite does not.183 Whole-blood analysis measures selenium in both the intracellular and extracellular compartments and may be the best assessment if selenium excess is suspected. Serum and plasma are the most commonly assessed, despite the fact that serum levels may decrease during acute-phase activation or chronic inflammation.184 Lower levels of serum selenium have been associated with an increased risk of anemia in adults over 65 years old.185 Erythrocyte levels remain stable, even as serum or plasma levels decrease, and may provide a better assessment of recent dietary intakes over the life span of the RBC (60–120 days).186 Urinary selenium levels reflect recent dietary and environmental exposures.187 After the injection of 2,3 dimercaptopropane-1-sulfonate (DMPS), less urinary selenium is excreted by subjects with amalgams, which indicates that selenium may bind to mercury.188 Hair selenium has been correlated with plasma levels in Polish subjects.189 Altered hair selenium levels have been demonstrated in subjects with nonalcoholic fatty liver disease190 and hyperlipidemia,191 compared with controls. Hair is easily contaminated from external sources, and selenium from antidandruff shampoos may greatly increase hair selenium levels.192 

Zinc Zinc is an essential cofactor and catalyst in approximately 300 enzymes.12,193,194 Zinc, cysteine, and histidine combine to form folded “zinc finger” compounds used in cellular metabolism as a structural stabilizer in proteins and membranes or as a regulator of gene expression. Adequate zinc is required for normal growth and development. Zinc is also used during the conversion of vitamin A precursors, cell signaling, hormone synthesis, and nerve transmission. Blood plasma contains less than 1% of total body zinc, and 80% of plasma zinc is bound to albumin. Zinc in erythrocytes is present as the enzyme carbonic anhydrase; RBC levels are about 10 times greater than plasma levels. Zinc assimilation in the gastrointestinal tract is variable based on the availability of zinc in the diet; zinc absorption may range from 20% to 50% of the zinc in a sufficient diet and may increase to 100% absorption of the zinc in a deficient diet. Zinc uptake may be inhibited if large amounts of supplemental iron are taken simultaneously or due to inherited variations in the ZIP4 (SLC39A4) gene.195 Excess zinc is excreted into the gut and incorporated into stool or excreted by the kidneys. Zinc, in excess, has toxic effects.12,194,196 Excessive supplementation, accidental exposure from galvanized food or beverage containers, or industrial exposure to zinc-oxide fumes may all result in toxic levels of zinc. Symptoms of toxic levels of zinc ingestion may include headaches, abdominal pain, vomiting, diarrhea, and loss of appetite. Symptoms of inhalation (metal fume fever) may include fever, sweating, shortness of breath, nausea, fatigue, and myalgias 4 to 12 hours

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postexposure; symptoms then resolve after 12 to 24 hours in a zinc-free environment. Chronically high levels of zinc exposure may decrease copper levels and result in nerve damage. Chronic high doses of zinc (100–150 mg daily) block gastrointestinal copper assimilation and result in low blood copper levels. Signs and symptoms include erythrocyte microcytosis (small RBCs), neutropenia (low WBCs), poor immune responses, and an increased risk of urinary lithiasis (kidney stones).197 Higher zinc doses of 140 to 450 mg daily may alter iron metabolism and reduce levels of high-density lipoproteins. Local applications of zinc in the nasal passages may damage olfactory nerves; intranasal zinc sprays and gels are no longer recommended because the loss of smell may be permanent. Marginal zinc deficiency may be prevalent in developing countries or areas dependent on cereal grain-based diets high in phytate and fiber.193 In the United States and Canada, zinc deficiency may occur because of inadequate intake, increased excretion, or increased requirement.12,194 Zinc deficiency may occur because of poor diet, gastrointestinal malabsorption, chronic diarrhea, cystic fibrosis, liver disorders, alcoholism, diabetes mellitus, chronic kidney disease, sickle cell disease, HIV+ status, physical trauma, pregnancy, and lactation. Severe zinc deficiency may cause symptoms of intrauterine growth restriction, impaired development, short stature,198 loss of appetite, immune dysfunction, weight loss, delayed wound healing, taste abnormalities, poor concentration, and fatigue. Symptoms may progress to night blindness, hair loss, diarrhea, delayed sexual development, male hypogonadism, impotence, and eye lesions or skin lesions. The very young and very old may have an increased risk of zinc deficiency.12,194,199,200 Inherited variations in the metal-binding protein metallothionein 2A (MT2A-5 A/G) may result in GG phenotypes having lower zinc and, perhaps, higher copper and lead levels than the wild-type AA phenotype.201 Inherited variations in the ZIP4 zinc transporter (SLC39A4) may result in severe zinc deficiency (acrodermatitis enteropathica) with classic indications of low (4 mg/L), or from the overuse of fluoride-containing products such as powdered infant formula, tea (Camellia sinensis), fluoride supplements, or fluoridated dental products.237 Young children may be at risk if they swallow fluoridated toothpaste.12 Medications, such as anesthetics, antibiotics, antiinflammatories, and cancer treatments, may contain fluoride. 18F-fluorodeoxyglucose is used as an imaging agent for positron emission tomography (PET) scans.10 Low-salt diets may decrease the element’s excretion in the urine and increase fluoride retention. Symptoms of acute fluoride poisoning may include gastrointestinal symptoms and progress to excessive salivation, excessive lacrimation, sweating, and muscle weakness. Chronic ingestion of higher levels of fluoride may contribute to the risk of hypothyroidism.238 A recent meta-analysis indicates that in utero exposures may contribute to lower IQ levels at fluoride exposure levels considered safe for adults.239 The most obvious sign of chronic excess fluoride ingestion is fluorosis, the development of chalky, white patches on erupting teeth, which may stain yellow or brown. Continued exposure (plasma fluoride > 4 micromoles/L) may weaken or pit tooth enamel and progress in adults to osteosclerosis (excessive bone hardening), spinal exostosis (new abnormal bone growth), and genu valgum (knock-knee).240 Symptoms of skeletal fluorosis may include joint pain and stiffness and may progress to calcification of ligaments, immobility, muscle wasting, and spinal cord compression. The use of the antifungal voriconazole may result in symptoms of fluorosis.241 Low levels of fluoride are associated with an increased risk of dental caries.12,237 Dietary sources include bone-in marine fish (sardines, etc.), tea, grape juice, and crab. Fluoride may be measured in plasma or urine.12 Individuals drinking U.S. fluoridated water may have plasma fluoride levels of 0.1 to 0.4 mmol/L and urinary fluoride levels of 0.2 to 3.2 mg/L.242 Drinking water samples may also be assessed for fluoride concentration with laboratory analysis. For urine and water samples, a special fluoride-specific

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electrode is usually used to directly determine concentration. Tissue (blood) samples require special processing to remove the fluoride from the organic material before measurement. 

Lithium The element lithium is found sporadically in natural drinking water sources and is not considered an essential element, although it may have biological effects at low doses.10 Lithium is absorbed by the gastrointestinal tract and excreted from the kidneys much like sodium.243 Lithium has been shown to upregulate the expression of glutathione S-transferase244 and the antiapoptosis genes BCL2 and IRS2 in vitro. Lithium also down-regulates the proapoptosis genes Bcl2-associated agonist of cell death (BAD) and Bcl-2 homologous antagonist/killer (BAK1).10 Lithium has also been shown in vitro to inhibit the expression of glycogen synthase kinase-3β, an enzyme involved in Alzheimer’s disease pathogenesis. Lithium exposure may alter thyroid function; urinary lithium levels have been inversely associated with plasma concentrations of T4 and positively associated with TSH in women,245 and plasma levels of lithium carbonate have been associated with TSH levels in children.246 High levels of lithium carbonate are used as a pharmaceutical in the treatment of mania and bipolar disorder; responses to lithium therapy may depend in part on the patient’s ethnicity and inheritance of glutamate decarboxylase-like protein 1 (GADL1).10 GADL1 variants rs17026688, rs17026651, and IVS8 + 48delG may predict lithium response in patients of Han Chinese descent.247 Because of its chemical similarities to sodium, renal lithium conservation may be increased in dehydrated patients.243 Toxicity information is based on studies of lithium carbonate. High levels of lithium carbonate may result in lethargy, dizziness, weakness, poor coordination, slurring speech, gastrointestinal symptoms, confusion, or restlessness.248 Chronic exposure to high levels of lithium carbonate may impair renal and thyroid function. Blood levels greater than 2.5 mmol/L may result in tremors, muscle rigidity, hyperreflexia, seizures, and renal failure. Prenatal exposure to lithium carbonate during the first trimester may result in the development of cardiac malformations.249 The use of medications such as acetazolamide, ACE inhibitors, angiotensin II receptor antagonists, antacids, caffeine, calcium channel blockers, NSAIDs, theophylline, or psychiatric medications such as haloperidol, methyldopa, and selective serotonin reuptake inhibitors may alter the metabolism of lithium carbonate.250 Symptoms of deficiency may affect the central nervous system, and behavioral disorders have been associated with low lithium levels.10 Population studies have associated lower levels of lithium exposure (2.0–5.0 μg/L) in drinking water with a higher risk of dementia, vascular dementia, and Alzheimer’s disease compared with populations with more than 10 μg/L in drinking water.251 No association has been found in population studies for the incidence of bipolar disorder and lithium levels in drinking water.252 Low hair lithium levels have been associated with heart disease, learning disabilities, and violent behavior.253 Lithium levels may be evaluated in serum,243 erythrocytes,254 urine,255 or hair.253 Serum is most commonly used to assess levels of lithium carbonate and may correlate with RBC levels.256 Urinary lithium values were found to range from 11.0 to 50.5 μg/L in a Japanese population. Hair lithium levels averaged 0.063 μg/g in a study of U.S. adults, and hair levels may correlate with lithium supplementation. 

Vanadium Vanadium is not currently considered an essential nutrient cofactor for any human enzyme, although it is essential for some rodents (rats) and other mammals.257 Because of this, animal studies using this element may not translate directly into human populations.

Vanadium may compete with phosphate-binding sites in human enz­ ymes.258 Increasing evidence suggests vanadium may have effects on cell metabolism and immune responses, particularly humoral B cell responses,259 and sodium–potassium ATPase.260 The oxidation state of vanadium may determine whether it is found in the cell or the plasma. VanadiumIV binds to transferrin in the blood and is primarily found in the plasma. Intracellular vanadium is found primarily in the kidneys, spleen, bones, and liver, and is typically found as vanadiumIV or vanadiumV. Small human studies indicate that vanadium may result in minor improvements in glucose metabolism, glycogen synthesis, and HbA1c levels in subjects with type 2 diabetes; however, vanadium may also increase triglyceride levels, and large, well-controlled studies are needed to confirm findings and establish dosing.261,262 Assimilation of vanadium by the gastrointestinal tract is poor (3%–20%). Vanadium is primarily excreted through the kidneys. High levels of vanadium exposure, either ingested or inhaled, have toxic effects.263–265 Toxic vanadium compounds may be encountered in industrial settings and released into the environment as industrial waste (coal emissions, fly ash, fuel oils, jet exhaust).266 Several organic vanadium compounds have been tested as treatment agents for diabetes and cancer. Inhalation of vanadium compounds may result in cough, sputum, exertional dyspnea, wheezing, headache, nausea, palpitations, nosebleed, abnormal breath sounds (wheezes, rales, rhonchi), eye irritation, and throat inflammation. Ingestion of vanadium compounds may result in headache, nausea, and diarrhea. Chronic high levels of exposure may progress to distal tremors (hands), diarrhea, blood cell abnormalities, hair and nail changes, green-hued tongue, hypertension, and enlarged liver. Industrial exposures to vanadium compounds have been associated with altered response times, cognition, and mood in Chinese factory workers.267 Although vanadium deficiency has not been studied in humans, low levels of vanadium have been associated with several chronic diseases. A study of Chinese industrial workers associated low levels of vanadium with an increased risk of atherosclerosis (higher cholesterol, lower high-density lipoprotein C [HDL-C], poor apoB:apoA1 ratios); the association was strongest in male subjects. Another study found an inverse correlation between new-onset type 2 diabetes in Chinese individuals and plasma vanadium levels.268 The subjects with the lowest levels of vanadium had the highest risk of diabetes. Food sources of vanadium include mushrooms, shellfish, peppers, parsley, dill weed, grain, and grain products. Vanadium levels may be evaluated in whole blood, serum, urine, or hair.265 Serum or whole blood is preferred because very little vanadium is found in RBCs. The average serum concentration due to dietary vanadium exposures is less than or equal to 2 μg/L. The average urinary vanadium level from normal background exposures (based on study controls) was found to be 2.7 μg/L. Women in the highest third of urinary vanadium concentration were shown to have a lower risk of breast cancer (64%–40%) compared with those in the lowest third.269 Hair levels of vanadium have not been correlated with ingestion in studies of children exposed to elevated vanadium in drinking water. 

CONCLUSION Newer technologies and methodologies continue to improve the detection of mineral elements. Testing for mineral excess or deficiency may be an important step in the diagnosis of patients and may be necessary to confirm the effectiveness of supplementation or dietary changes.270,271 It is important to remember that a laboratory result is only as good as the laboratory performing the assay. Reputable laboratories will have quality assurance and quality control procedures in place32,272 and will participate in third-party proficiency testing when available.

CHAPTER 23  Proper collection and analytic procedures must be followed to ensure accurate results. For mineral element analysis, such procedures may include the preanalytical preparation of hair samples.273 For blood samples, element-free collection equipment is essential to prevent contamination and false high results. Careful preparation of separated blood components is also required to ensure the accuracy of results. Urinary samples may occasionally be contaminated by personal hygiene products, and hair may be easily contaminated by minerals in bathing water or by elements in hair products.274 The interpretation

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of results must always include the consideration of the patient’s history and physical condition because, in the end, it is the patient who is treated, not the laboratory results.273

REFERENCES See www.expertconsult.com for a complete list of references.

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24 Mold Exposure Assessment Ann Shippy, MD OUTLINE Introduction, 208 Definitions, 208 Challenges, 208 Symptoms to Consider in Mycotoxin Illness from Contaminated Food or Inhalation, 209 Positions of National and International Organizations on Mold and Nonrespiratory Conditions, 209 Water-Damaged Buildings, 209 Assessment of Mold Exposure, 211 IgG or IgE Allergy Serum Testing, 211 Mycotoxin Urinary Levels, 211

INTRODUCTION Chronic exposure to environmental toxins, including mycotoxins and microbial volatile organic compounds (mVOCs) from mold, is an important emerging area of medicine. Despite recent advances in the technology to test for mold and mycotoxins, there is much more that needs to be known to provide the best care. Identifying patients affected by mold is challenging because there are no standards of care for testing or treatment. Many physicians are not even aware of the effects of mycotoxins, and medical organization statements have not incorporated the most recent research and testing capabilities in their position statements and recommendations. How many years of research and legal battles did it take to identify smoking tobacco as a health hazard and then to change public policy? Most people now realize that breathing in smoke and air pollution is detrimental to their health. At this time, most people and healthcare providers do not realize the harmful effect of the inhalation or ingestion of mold toxins from buildings that are commonly water damaged and many food products. It is likely that, one day, we will look back at mold exposures in food and buildings in the same way we look at the danger of tobacco use now—it seems so obvious. 

DEFINITIONS Mycotoxins: Mycotoxins are fungal secondary metabolites that bioaccumulate, leading to carryover and concentration into animal fluids, organs, and tissues. As a consequence, mycotoxin determination in biological samples from humans and animals has been reported worldwide. Because most mycotoxins show toxic effects at low concentrations and considering the extremely low levels present in biological samples, the application of reliable detection methods is required.1 mVOCs: mVOCs are chemicals with low molecular weights, high vapor pressure, and low water solubility produced by fungi and bacteria during metabolism. These chemical characteristics allow mVOCs to easily evaporate into the air or “off-gas,” and they may have an odor. Volatile organic compounds (VOCs) can be produced through industrial or biological processes. In the industrial setting, VOCs are

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Inflammatory Markers and Hormones, 211 Proteomics, 211 Genetics, 211 Visual Contrast Sensitivity Testing, 211 Laboratory Testing Technology, 211 Treatment, 213 1. Avoidance, 213 2. Enhance Detoxification Pathways, 213 3. Comprehensive, Integrated Care, 214 Conclusion, 214

commonly used or are created as by-products in the manufacture of paints, pharmaceuticals, refrigerants, petroleum fuels, dry cleaners, furniture, household cleaners, and other common products. 

CHALLENGES 1. There has been little research on the effects of chronic exposure to low levels of mycotoxins and mVOCs in humans. This means much of the clinical application has to be extrapolated from primarily cell and animal studies and a few human studies. 2. The technology to detect mycotoxins and mVOCs in humans or the environment is in its infancy. Thus there are no defined, well-accepted protocols. There is considerable noise and confusion over the best practices, although there has been moderate progress in the past decade in developing technology to detect mycotoxins in food, the environment, and humans. 3. There is a lack of research on how to treat patients affected by toxic mold most effectively and the best ways to monitor their progress. 4. There is a lack of research to identify the safe levels of mycotoxins and mVOCs accounting for the synergy of other environmental toxins or the genetics and nutritional status of the individual. 5. The U.S. government and other governments and organizations, such as the World Health Organization (WHO), have not yet updated their policies based on progress with the testing technology that has been added in the past decade to improve the detection of mycotoxins and correlate them to human illness. Much more research needs to be funded. 6. Mycotoxin-induced illness is likely a significant health-damaging epidemic based on the high prevalence of water-damaged buildings and the extensive presence of mycotoxins in the food supply. 7. Addressing this epidemic may be an enormous financial burden because many buildings such as residences, schools, businesses, and governments that affect the health of their inhabitants are in need of extensive remediation for acceptable or optimal human health.

CHAPTER 24  8. The governmental regulations of mycotoxins in food vary greatly by country. Global standards are needed that account for the synergy of mycotoxins. This will also have a significant financial impact as even more batches of crops and products are deemed inedible.

Symptoms to Consider in Mycotoxin Illness from Contaminated Food or Inhalation At the time most government policies and medical organization statements were published, there was no testing available to correlate mycotoxins present in humans and the environment with human disease, and thus such policies are outdated. Most of the research on mycotoxins is done on animals or other organisms. Because controlling mold in animal feed is a challenging, ongoing worldwide issue, there is extensive animal research. Standard medical education teaches clinicians to consider mold only as an allergy or asthma issue or in the differential diagnosis for an infectious disease in immunocompromised patients, not as a toxicity issue. Certainly, mold infection is a recognized cause of morbidity and mortality in transplant patients on immunosuppression, patients on chemotherapy, and those with autoimmunity or immunodeficiency.2 Few health care providers are aware of the toxic effects of mold on their patients. As more health care providers gain experience in recognizing mold-related illness, emerging research is showing promise for identifying mold toxin exposure as an underlying contributor to many illnesses. Research estimates that up to 50% of residential and work environments in North America have had water damage3 and that mold exposure should be considered in all patients with any chronic respiratory condition. Of particular significance is the finding that in adult-onset asthma, two thirds of cases are caused by exposure to water-damaged buildings. The relationship of indoor mold exposure from water-damaged buildings to other health conditions has less research available. Mold exposure has been linked to neurotoxicity, autoimmunity, immunotoxicity, and cytotoxicity. The carcinogenic effects of food-borne mold contamination are well established. Research supports that environmental toxins drive disease in the general population, not just those who are genetically or nutritionally the most susceptible. Mycotoxins and mVOCs are joining the categories of pesticides, metals, solvents, and persistent organic pollutants in affecting health and longevity. 

Positions of National and International Organizations on Mold and Nonrespiratory Conditions World Health Organization

• “ Microbial growth may result in greater numbers of spores, cell fragments, allergens, mycotoxins, endotoxins, β-glucans and volatile organic compounds in indoor air. The causative agents of adverse health effects have not been identified conclusively, but an excess level of any of these agents in the indoor environment is a potential health hazard.”3 • Mycotoxins, or fungal toxins, are low-relative-molecular-mass biomolecules produced by fungi, some of which are toxic to animals and human beings. Mycotoxins are known to interfere with RNA synthesis and may cause DNA damage. Some fungal species may produce various mycotoxins, depending on the substrate. In the case of Penicillium, one such compound is penicillin, a strong antibiotic. Several mycotoxins (e.g., aflatoxin from Aspergillus flavus and Aspergillus parasiticus) are potent carcinogens. Many mycotoxins are immunotoxic, but the trichothecene mycotoxins are immunostimulating at low doses.4 Numerous mycotoxins have been classified by their distinct chemical structures and reactive functional groups, including primary and secondary amines, hydroxyl or phenolic groups, lactams, carboxylic acids, and amides. The mycotoxins that have perhaps received the most attention are the trichothecenes, produced by Stachybotrys chartarum. Bloom5

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209

showed that several mycotoxins produced by S. chartarum and Aspergillus versicolor (i.e., macrocyclic trichothecenes, trichodermin, sterigmatocystin, and satratoxin G) could be present in most samples of materials and settled dust from buildings with current or past damage from dampness or water damage. Charpin-Kadouch6 compared the levels of macrocyclic trichothecenes in samples from 15 flooded dwellings known to be contaminated with S. chartarum or Chaetomium and a group of nine dwellings without visible mold. The level of macrocyclic trichothecenes was significantly higher in floor dust from the moldy houses than from the reference dwellings; the levels in wall samples from moldy houses were also higher. 

Centers for Disease Control and Prevention7 • A  link between other adverse health effects, such as acute idiopathic pulmonary hemorrhage among infants, memory loss, or lethargy, and molds, including the mold S. chartarum (Stachybotrys atra), has not been proven. Further studies are needed to find out what causes acute idiopathic hemorrhage and other adverse health effects. • Standards for judging what is an acceptable, tolerable, or normal quantity of mold have not been established. • In summary, S. chartarum (S. atra) and other molds may cause health symptoms that are nonspecific. At present, there is no test that proves an association between S. chartarum (S. atra) and particular health symptoms. Individuals with persistent symptoms should see their physician. However, if S. chartarum (S. atra) or other molds are found in a building, prudent practice recommends that they be removed. 

U.S. Environmental Protection Agency The U.S. Environmental Protection Agency (EPA) website has extensive resources to address identifying, preventing, and remediating water damage and mold, plus guidelines for schools. However, at the time of this writing, the medical content has not been updated since 2004. 

Water-Damaged Buildings Water-damaged buildings expose their occupants to a diverse range of toxins, with many physiologically damaging effects. Chemical, microbial, and physical processes that break down building materials produce toxins. Tables 24.1 and 24.2 list the metabolite toxins released, organisms involved, physiological effects induced, and disease associations. Tables 24.3 and 24.4 shows that bacterial growth also releases toxins in water-damaged buildings. The strongest correlations to mold exposure and symptoms are neurological and immunological, but such exposure can affect all systems of the body. Food-borne mycotoxins have been shown to cause cancer, impaired child growth, neural tube defects, immunotoxicity, gastroenteritis, and renal disease.8 Studies comparing mycotoxins with pesticides show that mycotoxins can be more toxic than pesticides.9 Even more concerning is the research showing that fungal metabolites have synergistic genotoxic and other harmful effects.10 mVOCs are low-molecular-weight compounds and include numerous alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. They diffuse into the air and enter the body through the lungs and skin. mVOCs are even more toxic than the chemicals traditionally thought of as being industrial toxins. A study comparing fungal VOCs showed a greater toxic effect than formaldehyde, xylene, benzene, and toluene.11 I-octen-3-ol studies predict it to be more toxic to human embryonic stems cells than toluene.12 Increased levels of biomarkers such as myeloperoxidase, lysozyme, and eosinophil cationic protein are related to symptoms of headache, nausea, and mucosal irritation as inflammation increases from exposures. Neurotoxicity is clearly associated with mold exposure and other toxin exposures. One study evaluated neurobehavioral and pulmonary

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TABLE 24.1  Toxic Metabolites Produced by Bacteria Isolated From Water-Damaged Materials

and Indoor Air Metabolite

Organisms

Physiological Effects

Disease

Valinomycin Leptomycin B Toxic peptide Mitochondrial toxin Mitochondrial toxin Cytostatic compounds

Streptomyces griseus Streptomyces species Bacillus amyloliquefaciens Bacillus pumilus Nocardiopsis species Coculture of S. chartarum and S. californicus

Mitochondrial poison Inhibition of inducible nitric oxide synthetase Depolarized transmembrane. Decreased ATP and NADH cell death Disruption of mitochondrial membrane Disruption of mitochondrial membrane Cytotoxic compounds that are just as toxic as doxorubicin and AMD

Unknown Unknown Unknown Unknown Unknown Unknown

AMD, actinomycin D; ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide. Adapted from Thrasher JD, Crawley S. The biocontaminants and complexity of damp indoor spaces: more than what meets the eyes. Toxicol Ind Health. 2009;(9-10):583-615

TABLE 24.2  Mycotoxins Produced by Toxic Molds Metabolite

Organisms

Physiological Effects

Disease

Gliotoxin

Aspergillus fumigatus, terres, flavus, niger; Trichoderma virens; Penicillium spp.; Candia albicans Aspergillus flavus

Immune toxicity, immunosuppression, neurotoxicity

Invasive aspergillosis

Liver pathology and cancer; immune toxicity; neurotoxicity Lung disease; neurotoxicity; tremors; immune toxicity Immunosuppression

Carcinogenesis

Aflatoxin B1, kojic acid, aspergillic acid, nitropropionic acid Fumigaclavines, fumitoxins, fumitermorgens, verruculogen, gliotoxin Ochratoxin A Urinary tract tumors Aspergillosis Ochratoxin A Penicillic acid, xanthomegnin, viomellein, vioxanthin Sterigmatocystin, 5-methoxysterigmatocystin Chaetomiums Chaetoglobosum A and C Griseofulvin Dechlorogrseofulvins Trichodermin Trichodermo Mycophenolic acid Botryodiploidin Patulin, citrinin, chaetoglobosin, roquefortine C Verrucosidins Penicillic acid, nephrotoxic glycopeptides Trichothecenes Trichodermol, trichodermin, gliotoxin, viridin Fumonisins Spirocyclic Drimanes, roridin Satratoxins (F, G, H) Hydroxyroridin E Verrucarin J, trichodermin, dolabellanes, altrones B and C, stachybotrylactams

A. fumigatus

Aspergillosis Balkan endemic nephropathy (BEN) BEN

A. niger Penicillium verrucsom Aspergillus ochraceus

Lung disease Nephropathology

Aspergillus versicolor

Liver pathology and cancer

Carcinogenesis

Chaetomium globosum Memnoniella echinata

Cytotoxicity Cell division Carcinogenesis?

Unknown Unknown Unknown Reproductive toxin Hypersensitivity?

Penicillium brevicompactum Penicillium expansum

Protein synthesis inhibition Cytotoxic; mutagen Immune toxicity; cytotoxic

Penicillium plonicium

Cytotoxicity

Trichoderma spp.

Trichothecene toxicity Immunotoxicity

Fusarium verticillioides (aka moniliforme) Stachybotrys chartarum

Neural tube defects in animals and humans Respiratory bleeding Protein synthesis inhibition Neurotoxicity Cytotoxicity Immune toxicity

Urinary tract damage Tumors

Unknown Unknown Tremors Tremors Nephropathology Unknown Immune impairment Central nervous system (CNS) birth defects Pulmonary bleeding

Table 24.2 demonstrates that mycotoxins disrupt mitochondrial function; misbalance nitric oxide synthesis; and create inflammatory mediators, neurotoxicity, cytotoxicity, immune suppression, carcinogenesis, and mutagenesis. This long list can cause patients’ symptoms to be diverse and complex. Adapted from Campbell AW, Thrasher JD, Gray MR, Vojdani A. Mold and mycotoxins: effects on the neurological and immune systems in humans. Adv Appl Microbiol. 2004;55:375–406.

CHAPTER 24 

TABLE 24.3  Symptoms Caused by Mold

Toxicity/Water-Damaged Buildings

Mold Exposure Assessment

211

ASSESSMENT OF MOLD EXPOSURE IgG or IgE Allergy Serum Testing

Symptom

% in Exposed Population

% in Controls

p-Value

Memory problems Spaciness Excessive fatigue Coughing Slurred speech Weak voice Watery eyes Lightheadedness Dizziness Weakness Headache Throat discomfort Sinus discomfort Coordination problems Nasal symptoms Bloating Visual changes Rash

5.1 4.8 5.8 4.6 4.5 4.1 4.6 4.4 4.3 4.2 5.2 4.5 4.7 4.0 5.1 4.2 3.9 3.9

3.3 3.2 4.3 3.2 3.1 2.8 3.4 3.2 3.1 3.0 4.1 3.4 3.6 2.9 4.1 3.2 2.9 2.9

0.0002 0.0007 0.0001 0.001 0.002 0.003 0.004 0.006 0.005 0.008 0.005 0.008 0.01 0.01 0.02 0.02 0.02 0.02

Adapted from Campbell AW, Thrasher JD, Gray MR, Vojdani A. Mold and mycotoxins: effects on the neurological and immune systems in humans. Adv Appl Microbiol. 2004;55:375–406; Pizzorno J, Shippy A. Is mold toxicity really a problem for our patients? part 2-nonrespiratory conditions. Integr Med (Encinitas). 2016 Jun;15:8-14.

impairment via comparison among three groups: (1) those exposed to indoor molds, (2) those exposed to chemicals, and (3) “unexposed” community referents.13 Both the mold- and chemical-exposed groups had similar findings of decreased balance, longer reaction times, increased blink reflex latency, increased color discrimination errors, decreased visual field, and reduced grip strength; measures of cognitive and memory performance were abnormal. Another study of individuals exposed to mold in their homes found multiple neurological deficits in 70% and abnormalities in T and B cells in more than 80% of the patients.14 A study of individuals working in a well-documented water-damaged school building compared with “unexposed” controls found statistically significant loss of visual contrast sensitivity (VCS), a sensitive measure of neurodysfunction, as well as increased respiratory problems.15 Exposure to mold/damp buildings increases the production of multiple inflammatory molecules and alters immune function mediators. The immune systems of those working in damp buildings react to exposure with a 2- to 1000-fold increased production of a wide variety of these inflammatory/immune mediators.16 Animal studies clearly show mold-induced immunotoxicity as well. In some cases, multiple sclerosis could be a mold toxin disease from gliotoxin produced by various species of Aspergillus and Candida. Gliotoxin suppresses immune function, increases the permeability of the blood–brain barrier, and is highly neurotoxic.17 In a study on chronic fatigue syndrome (CFS), a high correlation was found between the presence of mycotoxins in the patient’s urine and having a diagnosis of CFS. Of participants, 93% had one mycotoxin present, and 30% had two or more mycotoxins present.18 Importantly, as the incidence of autoimmune disorders increases, cases of autoimmune diseases and related symptoms have been reported among the occupants of damp buildings.19 When seeing patients with autoimmune diagnosis, it is important to consider mold exposure as an underlying trigger that is potentially treatable. 

IgG or IgE allergy serum testing is an older method, but is sometimes helpful in raising the suspicion of current mold exposure. Some practitioners also use it to see if IgE and/or IgG levels are reduced with treatment, to evaluate the effectiveness of remediation/avoidance of exposure, and to consider immunotherapy. It is not conclusive, but levels of antibodies can correlate with the types and levels of mold the patient is being exposed to. 

Mycotoxin Urinary Levels The latest acceptable technology tests urine samples. Results are not conclusive if negative because all mycotoxins cannot yet be tested for. See the advantages and disadvantages of the two available technologies in Table 24.5. 

Inflammatory Markers and Hormones Inflammatory markers and hormones can be indicators for toxic exposures but are not conclusive if positive or negative. They can be helpful in monitoring a patient’s progress. These markers are part of the Shoemaker protocol. 

Proteomics Proteomic has promise in the assessment of mold exposure, but currently this approach is used only in research and is expensive. 

Genetics Genetic testing can be helpful to establish individual treatment programs. Consider human leukocyte antigen (HLA) type, methylation, P450, COMT, glutathione, NAT, VDR, and mitochondrial and histamine single-nucleotide polymorphisms (SNPs). Toxins affect individuals in different ways depending on their genetics, synergistic toxins present, and nutritional status. Early genetic testing can help identify those most susceptible to mold toxins and other environmental toxins. 

Visual Contrast Sensitivity Testing Visual contrast sensitivity (VCS) measures the ability to see details at low contrast levels. Although it is useful for early detection of neurodegeneration, it does not differentiate the cause. Biotoxins reduce available oxygen to the optic nerves as a result of reduced blood flow, which can affect the ability to detect the “edge” between light and dark and lead to a reduction in night vision and increased light sensitivity. This is an easily available and inexpensive test. However, it is a nonspecific test of neurological function (i.e., not diagnostic for mycotoxin illness). A positive test may reveal a 92% chance that a patient has biotoxin illness, but again, it does not determine which toxin—it could be mold toxins or an environmental neurotoxin, such as mercury. Positive tests usually indicate mold exposure but can also be attributed to Lyme disease or other biotoxins. Testing needs to be conducted at a distance of 18 inches from the screen and should be done in the daytime. False positives can occur with cataracts or other vision abnormalities 

Laboratory Testing Technology Testing for the mycotoxin load present in humans via sampling tissue and body fluids is still very limited. There are likely hundreds of mycotoxins, possibly even an order of magnitude more, but only a few can be commercially tested for in human samples or the environment, except in research laboratories. Qualitative polymerase chain reaction (QPCR) can now be used to detect and quantify the presence of 45 molds in human tissue and the environment.

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TABLE 24.4  Health Hazard Evaluation Report HETA 2005-0135-3116, Alcee Fortier Senior High

School New Orleans, Louisiana, September 2010, Department of Health and Human Services, Centers for Disease Control and Prevention, Workplace Safety and Health, National Institute for Occupational Safety and Health AFSHS

WHHS

Prevalence Ratio

p-Value

Cough Wheezing or whistling in chest Chest tightness Unusual shortness of breath

35 (43) 19 (23) 22 (27) 19 (24)

11 (10) 2 (2) 0 4 (4)

4.16 (2.26, 7.68) 12.13 (2.91, 50.62) +inf (7.69, +inf) 6.22 (2.20, 17.56)

14 μmol/L by their definition) in a group of 1160 elderly (ages 67–96 years) individuals in the Framingham Heart Study. The study also indicated that plasma homocysteine levels increased with age.57 A number of interrelated atherogenic mechanisms are thought to be involved with hyperhomocysteinemia. These include advanced thickening and smooth muscle cell proliferation of endothelial vessel wall intima, enhanced lipid deposition in the vessel wall, forced detachment of endothelial cells, activation of leukocytes and thrombocytes, increased low-density lipoprotein oxidation, initiation of platelet thromboxane synthesis, enhanced oxidative stress induced by peroxide formation during homocysteine oxidation, and prothrombotic coagulation interference.62,63 One way homocysteine assists this process is by the generation of hydrogen peroxide.64 By creating oxidative damage to low-density lipoprotein cholesterol and endothelial cell membranes, hydrogen peroxide can then catalyze injury to vascular endothelium.64,65 Nitric oxide and other oxides of nitrogen released by endothelial cells (also known as endothelium-derived relaxing factor) protect endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation. However, as homocysteine levels increase, this protective mechanism can become overloaded, allowing damage to endothelial cells to occur.65–67 Because of the role of sulfate compounds in the formation of amino sugars needed to form the basement membrane of blood vessels, high levels of homocysteine are likely to contribute to the formation of blood vessels that are more susceptible to oxidative stress.67 The end result of the combination of oxidative damage and endothelial collagen instability can be the formation of atherosclerotic plaques. Decreased plasma folate levels are correlated with increased levels of homocysteine, as well as a subsequent increased incidence of CAD. In a 15-year Canadian study of CAD mortality in 5056 men and women ages 35 to 79 years, lower serum folate levels were correlated with a significantly increased risk of fatal CAD.68 In a cohort from the Framingham Heart Study, concentrations of folate and P5P were inversely correlated with homocysteine levels and the risk of

994

SECTION 5 

Syndromes and Special Topics

extracranial carotid artery stenosis.57 Low P5P and low vitamin B12 have also been linked with hyperhomocysteinemia and a significantly increased risk of CAD.51 Another study of 160 cardiac transplantation patients followed for an average of 28 days found that the high homocysteine levels seen in 99 of these patients surprisingly demonstrated no causal role in the atherothrombotic vascular complications of transplantation. Vitamin B6 deficiency was seen in 21% of recipients with, and in 9% without, cardiovascular complications or death, or both. Compared with patients with normal B6 levels, there was a 2.7-fold increase in untoward cardiac events for those patients with B6 levels less than or equal to 20 nmol/L.69 Remethylation of homocysteine and the subsequent formation of SAMe are critical for biosynthesis of l-carnitine, CoQ10, and creatine. Similarly, the transsulfuration pathway must be functioning properly for optimal biosynthesis of cysteine, GSH, pantethine, and taurine. All of these nutrients are used clinically to reduce oxidative stress, improve risk factor markers, or treat heart disease. Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine.18 

Peripheral Vascular Disease Elevated homocysteine levels have been established as an independent risk factor for intermittent claudication and deep vein thrombosis. Elevated homocysteine levels corresponded with an increased incidence of intermittent claudication and decreased serum folate levels in a study of 78 patients with intermittent claudication.70 A fourfold increase in the risk of peripheral vascular disease was noted in individuals with hyperhomocysteinemia compared with those with normal homocysteine levels.71 A group of researchers in the Netherlands found high homocysteine levels to be a significant risk factor for deep vein thrombosis, with a stronger relationship among women than men.72 An increased risk of peripheral vascular occlusion was noted in women taking oral contraceptives, which might be linked to the significantly increased homocysteine levels in women so affected. It is already known that oral contraceptives can cause declines or deficiencies in vitamins B6, B12, and folate, nutrients integral to the processing of homocysteine. Laboratory assessment of plasma homocysteine levels may be helpful to detect women who may be predisposed to peripheral vascular occlusion while on oral contraceptives.73 

Stroke Stroke patients have significantly elevated homocysteine levels compared with age-matched controls,74 with a linear relationship between risk of stroke and homocysteine levels75 and a significant decrease in blood folate concentrations in those with elevated homocysteine.76 One investigation revealed that people with a dietary intake of at least 300 mcg/day of folic acid reduced their risk of stroke and heart disease by 20% and 13%, respectively, compared with those who consumed less than 136 mcg of folic acid per day.77 

Pregnancy Biochemical enzyme defects and nutritional deficiencies can contribute to neural tube defects (NTDs), as well as other negative pregnancy outcomes, including spontaneous abortion, placental abruption (infarct), preterm delivery, and low infant birth weight. Evidence has suggested that derangement of methionine-homocysteine metabolism could be the underlying mechanism of pathogenesis of NTDs and might be the mechanism of prevention observed with supplementation of folic acid.78,79 It has been firmly established that a low dietary intake of folic acid increases the risk for delivery of a child with an NTD and that periconceptional folic acid supplementation reduces the occurrence of NTDs.80–86 Research also indicates that supplemental

folic acid intake results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal infections.87–90A derangement in methionine-homocysteine metabolism has also been correlated with recurrent miscarriage and placental infarcts (abruption).91 The amino acid homocysteine, when elevated, might be a teratogenic agent contributing to congenital defects of the heart and neural tube. Evidence from experimental animals lends support to this belief. When avian embryos were fed homocysteine to raise serum homocysteine to over 150 nmol/mL, dysmorphogenesis of the heart and neural tube, as well as of the ventral wall, was observed.92 Because homocysteine metabolism, through the remethylation and transsulfuration pathways, affects several biochemical pathways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous systems, it is not surprising that these other nutrients have been linked to complications of pregnancy in animal models and humans. Low plasma vitamin B12 levels have been shown to be an independent risk factor for NTD.93,94 Methionine has been shown to reduce the incidence of NTD by 41% in an animal model when administered on days 8 and 9 of pregnancy.95,96 This evidence indicates that a disturbance in the remethylation pathway with a subsequent decrease in SAMe may be a contributing factor to these complications of pregnancy. PC, due to its role as a precursor to acetylcholine and choline, is acknowledged as a critical nutrient for brain and nerve development and function.97–99 Because the metabolic pathways of choline (via betaine), methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine, a disturbance in the metabolism of either of these two methyl-donor pathways, due to limited availability of key nutrients or decreased enzyme activity, directly affects the body’s ability to optimize levels of SAMe. Evidence suggests that women with a history of NTD-affected pregnancies have altered folate metabolism.100–103 Patients with a severe congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and adenosylmethionine in their cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord.2,104 Because of its direct effect on the activation of folic acid to its methyl derivative, a milder version of this enzyme defect is also strongly suspected to increase the incidence of NTDs.105 It is established that high vitamin A intake during the first 2 months of pregnancy is associated with a severalfold higher incidence of birth defects.106,107 Although the mechanism of action remains to be elicited, in an animal model, the activity of hepatic MTHFR was suppressed with high vitamin A levels, suggesting that its teratogenic effect during early pregnancy might be associated with a subsequent derangement in the remethylation of homocysteine.108 Because a more significant correlation has been found between high homocysteine levels in women experiencing placental abruption, infarction, and spontaneous abortion than in control women, and homocysteine and CoQ10 synthesis depend on the methionine-SAMe-homocysteine pathway, it is possible that low CoQ10 and elevated homocysteine independently found in complicated pregnancy may also be found in related conditions.109,110 Nutritional intervention with the cofactors required for optimal metabolism of the methionine-homocysteine pathways offers a new integrated possibility for primary prevention of NTD and several other complications of pregnancy. Supplementation with betaine and the active forms of cobalamin and folic acid, such as methylcobalamin and folinic acid, along with riboflavin-5′-phosphate (because of its role as a cofactor for the MTHFR enzyme), may play a significant role in reducing or preventing these emotionally devastating outcomes.

CHAPTER 134  There is an effect of thyroid hormone on folate and vitamin B12dependent biochemical processes during early growth and development. Higher thyroid function is associated with higher homocysteine concentration in pregnant women and in neonates. 

Neurological and Mental Disorders In addition to the known effect of homocysteine on the cardiovascular system and micronutrient biochemical pathways, numerous diseases of the nervous system are correlated with high homocysteine levels and alterations in vitamin B12, folate, or vitamin B6 metabolism, including depression, schizophrenia, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease (AD), and cognitive decline in the elderly. Methylation reactions via SAMe, including methylation of DNA and myelin, are vitally important in the CNS. The neurological complications of vitamin B12 deficiency are likely due to a reduction of activity of the vitamin B12-dependent enzyme methionine synthase and the subsequent reduction of SAMe production. The CNS lacks the alternate betaine pathway of homocysteine remethylation; therefore if methionine synthase is inactivated, the CNS has a greatly reduced methylation capacity.111 Other causes of reduced methionine synthase activity include folic acid deficiency and nitrous oxide anesthesia exposure.112 Homocysteine has also been found to be a neurotoxin, especially in conditions in which glycine levels are elevated, including head trauma, stroke, and vitamin B12 deficiency.113 Homocysteine interacts with the N-methyl-d-aspartate receptor, causing excessive calcium influx and free radical production, resulting in neurotoxicity.94 The neurotoxic effects of homocysteine or reduced methylation reactions, or both, in the CNS contribute to the mental symptomatology seen in vitamin B12 and folate deficiency. Increased homocysteine levels can also be seen in schizophrenics.114 Significant deficiencies in vitamin B12 and folate are common in the elderly population and can contribute to a decline in cognitive function.115–117 An investigation of cognitive ability in older men (54–81 years old) found poorer spatial copying skills in those with higher homocysteine levels. Better memory performance was correlated with higher vitamin B6 levels.118 Vitamin B12 deficiency and increasing severity of cognitive impairment have been seen in patients with AD compared with controls and patients with other dementias.119 In a study of 52 AD patients, 50 hospitalized nondemented controls, and 49 elderly subjects living at home, patients with AD were found to have the highest homocysteine levels and the highest methylmalonic acid (an indicator of vitamin B12 deficiency) levels.120 In another Framingham study cohort with an average of 8 years’ follow-up, dementia developed in 111 of 1092 nondementia subjects, including 83 who were diagnosed with AD. The adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the logarithmically adjusted homocysteine value. The relative risk of AD was 1.8 per increase of 1 standard deviation at baseline and 1.6 per increase of 1 standard deviation 8 years before baseline. Additionally, in those with a plasma homocysteine level that was greater than 14 μmol/L, the risk of AD nearly doubled.121 In a study of 741 psychogeriatric patients, high plasma homocysteine levels were found in demented and nondemented patients; however, only demented patients also had lower blood folate concentrations compared with controls. Patients with concomitant vascular disease had significantly higher plasma homocysteine than those without diagnosed vascular disease. Significantly higher homocysteine levels, compared with controls, have also been found in Parkinson’s disease patients.122

Homocysteine Metabolism

995

Homocysteine’s effects on neurotransmitter metabolism, along with its potential reduction of methylation reactions, could be a contributing factor to the etiology of depression. Folate and vitamin B12 deficiency can cause neuropsychiatric symptoms, including dementia and depression. SAMe is used therapeutically as an antidepressant in Europe and was the third-most-popular antidepressant treatment in Italy in 1995.123,124 Long-term treatment of poststroke survivors with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (0.5 mg) was associated with a reduction in major depression in a 563-patient, randomized, double-blind, placebo-controlled trial.125 Methylation of myelin basic protein is vital to the maintenance of the myelin sheath. The worst-case scenario of folate and vitamin B12 deficiency includes demyelination of the posterior and lateral columns of the spinal cord, a disease process called subacute combined degeneration of the spinal cord (SCD).111 SCD can also be precipitated by nitrous oxide anesthesia, which causes an irreversible oxidation of the cobalt moiety of the vitamin B12 molecule and the subsequent inhibition of methionine synthase activity, a decrease in homocysteine remethylation, and decreased SAMe production.112 This has been treated using supplemental methionine, which further supports the theory of a nitrous oxide–induced biochemical block at methionine synthase.126 Particularly at risk for this condition are vitamin B12-deficient individuals who visit their dentist and receive nitrous oxide.112,127 Abnormal methylcobalamin metabolism is one of the proposed mechanisms for the pathophysiology of the demyelinating disease multiple sclerosis (MS). Deficiency of vitamin B12 has been linked to some cases of MS, and it has been suggested that dietary deficiency, or more likely, a defect in R-protein–mediated absorption or methylation of vitamin B12, might be a significant contributor to the pathogenesis of MS.128 Individuals with genetic variation in the 5,10-MTHFR gene are more susceptible to having a psychiatric disorder. The genetic variation MTHFR C677T was significantly associated with schizophrenia, bipolar disorder, and unipolar depressive disorder.129 

Diabetes Mellitus Homocysteine levels appear to be lower in individuals with type 1 diabetes mellitus. Forty-one subjects with type 1 diabetes (age 34.8 ± 12 years; duration of illness: 10.7 ± 11.1 years) were compared with 40 age-matched control subjects (age 34.2 ± 9.1 years). After an overnight fast, homocysteine was significantly lower (P = 0.0001) in the diabetic group (6.8 ± 2.2) than in the controls (9.5 ± 2.9). This difference was apparent in male and female subgroups.130 However, increased levels of homocysteine have been reported in type 1 diabetics with proliferative retinopathy131 and nephropathy.131,132 Evidence to date suggests that the metabolism of homocysteine is impaired in patients with non–insulin-dependent diabetes mellitus (NIDDM). After a methionine load, hyperhomocysteinemia occurred with significantly greater frequency in patients with NIDDM (39%) compared with age-matched controls (7%). The area under the curve over 24 hours, reflecting the total period of exposure to increased homocysteine, was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%) compared with controls (0%). The authors concluded that hyperhomocysteinemia was associated with macrovascular disease in a significant proportion of patients with NIDDM.133 Other researchers reported a correlation between increased homocysteine levels and the occurrence of macroangiopathy in patients with NIDDM. Intramuscular injection of 1000 μg methylcobalamin daily for 3 weeks reduced the elevated plasma levels of homocysteine in these individuals.134 Elevated homocysteine levels appear to be a risk factor for diabetic retinopathy in individuals with NIDDM. This might be due to a point

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mutation on the gene for the enzyme MTHFR.135,136 A significantly higher percentage of diabetics with retinopathy exhibit this mutation.137 Elevated homocysteine levels cause cell injury to the small vessels, which may contribute to the development of retinopathy, as well as macroangiopathy in the cardiovascular system.135 

Rheumatoid Arthritis Elevated total homocysteine levels have been reported in patients with rheumatoid arthritis (RA) and psoriasis. Twenty-eight patients with RA and 20 healthy age-matched control subjects were assessed for homocysteine levels while fasting and in response to a methionine challenge. Fasting levels were 33% higher in RA patients than in controls. Four hours after the methionine challenge, the increase in plasma homocysteine concentration was also higher in patients with RA.137 Another study found statistically significant increases in homocysteine in RA patients (P = 0.003), with 20% of the patients having homocysteine levels above the reference range.138 A mechanism for this increased homocysteine in RA patients has not been elucidated. Penicillamine, a common sulfhydryl-containing arthritis treatment, has been found to lower elevated homocysteine levels in vivo.139 

Psoriasis One study of 30 psoriasis patients and their matched controls were evaluated for blood concentrations of lipids, lipoproteins, acutephase reactants, homocysteine, and atherothrombotic markers. This study observed that more than 50% of the patients with psoriasis had homocysteine levels that were higher than 15 mmol/L, whereas only 20% of the control individuals were above this cutoff point. It was concluded that the mean levels of serum homocysteine, fibrinogen, fibronectin, intercellular adhesion molecules, plasminogen activator inhibitor, and autoantibodies against oxidized low-density lipoprotein were increased in psoriatic patients, whereas tissue plasminogen factor, vitamin B12, and folate levels were decreased significantly.62 Further investigation into both the prevalence of hyperhomocysteinemia and the mechanism of action affecting RA and psoriasis is necessary. 

Kidney Failure Because homocysteine is cleared by the kidneys, chronic renal failure, as well as absolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine, results in increased homocysteine levels. In 176 patients with end-stage renal disease on peritoneal or hemodialysis, homocysteine concentrations averaged 26.6 ± 1.5 μmol/L in patients with renal failure compared with 10.1 ± 1.7 μmol/L in normal subjects. Abnormal values exceeded the 95th percentile for normal controls in 149 of the patients with renal failure.140 Data also indicated that plasma homocysteine values represented an independent risk factor for vascular events in patients on peritoneal and hemodialysis. Patients with a homocysteine concentration in the upper two quintiles (>27.8 μmol/L) had an independent odds ratio of 2.9 (confidence interval, 1.4–5.8; P = 0.007) of vascular complications. Vitamin B levels were also lower in patients with vascular complications than in those without such complications.141 

Alcoholism and Ethanol Ingestion Chronic alcoholism is known to interfere with one-carbon metabolism. Because of this, it is not surprising to find that mean serum homocysteine levels are two times higher in chronic alcoholics than in nondrinkers (P 250.15(+) 24:424.10>377.25(+) 24:424.10>232.10(+)

3.409

400000

Water Damage

200000 100000 0 3.2

3.3

3.4

3.5

3.6

3.7

Determination by LC-MS/MS multi-analyte method Fig. 138.3  When molecules are fragmented in liquid chromatography with mass spectrometry (LC-MS/MS), they give a repeatable pattern that can be used to properly identify molecules.

from food contamination. The most important element for treatment is the avoidance of further exposure to water-damaged environments as well as contaminated foods. Using a licensed company to inspect and remediate the area is recommended. Remediation of contaminated areas is difficult because heat, ultraviolet (UV) light, bleach, ammonia,

Patients exposed to mycotoxins from mold may have two different conditions to treat. The first is the mycotoxin exposure, which can cause problems in many different tissues mentioned previously, and second is a possible infection and colonization of the fungi. To detoxify the mycotoxins, it is recommended to use a combination of glutathione, sauna, sequestering/binding agents, and antioxidants. Patients may also need to treat fungal infections and colonization. Detoxification of many mycotoxins is dependent on the endogenous molecule glutathione (GSH). For example, deoxynivalenol (DON) is a mycotoxin produced by certain Fusarium species that frequently infect corn, wheat, oats, barley, and rice, which can be detoxified when glutathione-S-transferase forms a conjugant with GSH and DON (Fig. 138.4). GSH is a tripeptide, which is made of glycine, cysteine, and glutamate. Mycotoxin toxicity is intensified in patients with glutathione transferase mutations (GSTP1 and GSTM).88 GSH can be introduced in several ways, including treating with GSH precursors such as N-acetyl cysteine and whey protein or with an oral liposomal, transdermal, intravenous, nebulized, or intranasal form of GSH. It is recommended to use GSH with sequestering agents because treatment with GSH has been shown to increase the mobilization of mycotoxins in the bloodstream.89 Sauna therapy has been used for centuries for the removal of toxins from the body. Some of the most commonly used saunas are dry-heat radiant saunas and far-infrared saunas. Both have been shown to be equally as good at removing toxins from the body. Infrared saunas have the advantage of inducing sweating at lower body temperatures. Sweating is important because many mycotoxins are lipophilic and can bind to lipid proteins, which will allow the mycotoxins to persist in the body for extended periods of time.90 The use of sauna has two benefits pertaining to detoxification of mycotoxins. First, it breaks the bonds between mycotoxins and lipids in the body, increasing the circulation of mycotoxins; and second, it provides a second excretion route because several mycotoxins have been found in human sweat.91 One study of 28 individuals who had been exposed to mycotoxins included a regimen of sauna, exercise, and physical therapy. In this study, all 28 individuals experienced significant improvement.92 Because both GSH treatment and sauna therapy increase the number of mycotoxins in the bloodstream, it is important to use sequestering agents in the treatment of mycotoxins. Many of these agents have shown efficacy in lowering mycotoxin levels. The most common sequestering agents used are activated charcoal, cholestyramine, clay, and chlorophyll. Activated charcoal has been used for about two decades in the treatment of mycotoxins. Multiple studies have validated the use of activated charcoal because of its high affinity for many different types of mycotoxins.93–95 Cholestyramine (CSM) is an anion exchange resin that works as a bile-acid–sequestering agent. Multiple studies have demonstrated that CSM treatment leads to a reduction of ochratoxin levels in the plasma and urine and increases the fecal excretion. CSM has also been shown to be safely tolerated in children.96,97 

Antioxidants One additional component of treatment that is necessary is the addition of antioxidant support. Mycotoxins exposure induces oxidative stress and cell as cellular DNA damage; however, antioxidants have been shown to decrease these effects. Patients treated with vitamins A,

CHAPTER 138 

Mycotoxin Exposure: Assessment and Treatment

1033

Mycotoxin Conjugational reaction GSH

Cytochrome P450

Glutathione S-transferase metabolites

Phase I

Phase II

Metabolite – GS-R conjugant

Enzymatic: GPx, catalase, superoxide dismutase R-O· R-OH H

O

H OH O

O HO O H

H

O

Non-enzymatic: GSH, MT, vitamin C,E

O

O HO O H

Antioxidant protection

Fig. 138.4 Scheme of the possible manner of deoxynivalenol detoxification. The first—and perhaps the most important—pathway used for the detoxifying of deoxynivalenol (DON) is cytochrome P450, which serves to catalyze the oxidation of organic substances. This pathway, however, can cause free hydroxyl groups of DON to be cleaved, producing DON-radical, which can be more dangerous. The DON-radical can be scavenged by enzymatic (glutathione peroxidase [GPx], catalase, superoxide dismutase) or nonenzymatic (reduced glutathione [GSH], metallothionein [MT], and vitamins) processes. Nevertheless, cytochrome P450 can be followed by Phase II, in which glutathione-S-transferase can form a conjugant with GSH and DON, which results in detoxification of the xenobiotic. (From Sobrova P, Adam V, Vasatkova A, Beklova M, Zeman L, Kizek R. Deoxynivalenol and its toxicity. Interdisc. Toxicol. 2010;3[3]:94–99. PubMed PMID: 21217881.) Exposure to mycotoxins

C, and E were shown to have better outcomes.98 Another antioxidant that has been shown to cause significant hepatoprotective activity is curcumin. In a rat study, rats that were exposed to aflatoxin B1 and treated with curcumin had significantly lower serum enzyme markers and higher levels of reduced glutathione, catalase, and glutathione peroxidase.99 

60 control mycotoxin positive *

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Patients who have high levels of mycotoxins in their bodies may also be suffering from fungal infections and colonization. This is usually caused by direct exposure to elevated levels of mold spores. Fungal infections can occur in many different parts of the body. The most common areas of infection are the sinus cavities, lungs, and intestine. One Mayo Clinic study found fungal growth in 96% of patients with chronic sinusitis. The types of mold found included Aspergillus, Penicillium, Alternaria, Cladosporium, Fusarium, and Cryptococcus. All of these molds are known to produce mycotoxins and cause significant diseases.100,101 One study demonstrated that antifungal drug therapies were useful in combating microbial pathogens detected by gas chromatography–mass spectrometry.102 Another recent study compared organic acid results from patients who had positive results on an LC-MS/MS mycotoxin with control subjects. This study demonstrated that certain markers are more elevated in patients who have been exposed to mycotoxins.103 The two categories of markers that were most pronounced were fungal markers and mitochondrial markers (Fig. 138.5). The two fungal markers that were significant were 5-hydroxymethyl-2-furioc and Furan-2,5-dicarboxylic, which are both fungal metabolites.104,105 These data indicate that certain organic acid tests that measure these markers may be helpful in diagnosing fungal infections.

Fig. 138.5  Exposure to mycotoxins.

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Syndromes and Special Topics

Treatment for fungal infections may involve several steps. The first step should be the avoidance of elevated spore counts and particulates through proper remediation and air filters. Second, antifungal medications have been shown to be efficacious. Multiple studies have used amphotericin B for the treatment of fungal infections.106–108 Other antifungals that have been used include ketoconazole, fluconazole, and itraconazole. For intestinal fungal infections, nystatin or liposomal nystatin may be a good alternative.109,110 

CONCLUSION Mycotoxin and fungal exposure can lead to many chronic illnesses, including fatigue, headaches, rashes, pulmonary infections, and even cancer. Mycotoxin exposure may also lead to many other coinfections because

of the mycotoxins’ abilities to impair immune system function. Because the concentrations of mycotoxin metabolites in human patients are quite low, testing has moved away from ELISA to the more sophisticated and sensitive LC-MS/MS technology. Treatment plans for patients exposed to mycotoxins that have been the most efficacious have been multifactorial, including binders, sauna, glutathione, antioxidants, and sometimes antifungal therapies. Treatment plans can take anywhere from a few months to a year to have sufficient removal of the toxins. However, most patients show significant improvements after removal of the mycotoxins.

REFERENCES See www.expertconsult.com for a complete list of references.

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72. Gillman IG, Clark TN, Manderville RA. Oxidation of ochratoxin A by an Fe-porphyrin system: model for enzymatic activation and DNA cleavage. Chem Res Toxicol. 1999;12:1066–1076. 73. Lea T, Steien K, Stormer FC. Mechanism of ochratoxin A-induced immunosuppression. Mycopathologia. 1989;107:153–159. 74. Boorman GA, et al. Myelotoxicity and macrophage alteration in mice exposed to ochratoxin A. Toxicol Appl Pharmacol. 1984;72:304–312. 75. Park SH, Kim D, Kim J, Moon Y. Effects of mycotoxins on mucosal microbial infection and related pathogenesis. Toxins (Basel). 2015;7:4484– 4502. https://doi.org/10.3390/toxins7114484. 76. Kupfahl C, Geginat G, Hof H. Gliotoxin-mediated suppression of innate and adaptive immune functions directed against Listeria monocytogenes. Med Mycol. 2006;44:591–599. https://doi.org/ 10.1080/13693780600815411. 77. Schlam D, et al. Gliotoxin suppresses macrophage immune function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis. MBio. 2016;7:e02242. https://doi.org/10.1128/mBio.02242-15. 78. Mitchell NJ, Bowers E, Hurburgh C, Wu F. Potential economic losses to the US corn industry from aflatoxin contamination. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2016;33:540–550. https://doi.org/10.1080/19440049.2016.1138545. 79. Solfrizzo M, Gambacorta L, Visconti A. Assessment of multi-mycotoxin exposure in southern Italy by urinary multi-biomarker determination. Toxins (Basel). 2014;6:523–538. https://doi.org/10.3390/toxins6020523. 80. Stahnke H, Kittlaus S, Kempe G, Alder L. Reduction of matrix effects in liquid chromatography-electrospray ionization-mass spectrometry by dilution of the sample extracts: how much dilution is needed? Anal Chem. 2012;84:1474–1482. https://doi.org/10.1021/ac202661j. 81. Avrameas S, Guilbert B. Enzyme-immunoassay for the measurement of antigens using peroxidase conjugates. Biochimie. 1972;54:837–842. 82. JSC T, GL L, Wong RC, Tse HY, eds. Drug-testing Technologies and Applications. Humana Press; 2005:29–69. 83. Escriva L, Font G, Manyes L, Berrada H. Studies on the presence of mycotoxins in biological samples: an overview. Toxins (Basel). 2017;9. https:// doi.org/10.3390/toxins9080251. 84. Griffiths WJ, Jonsson AP, Liu S, Rai DK, Wang Y. Electrospray and tandem mass spectrometry in biochemistry. Biochem J. 2001;355:545–561. 85. Liu WT, Kersten RD, Yang YL, Moore BS, Dorrestein PC. Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus. J Am Chem Soc. 2011;133:18010–18013. https://doi.org/10.1021/ja2040877. 86. Sleno L, Volmer DA. Ion activation methods for tandem mass spectrometry. J Mass Spectrom. 2004;39:1091–1112. https://doi.org/10.1002/jms.703. 87. Peitzch B, Haase M, Larson. J Environ Monitoring. 2012;14:908–915. 88. Sun CA, et al. Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. Carcinogenesis. 2001;22:1289–1294. 89. Hope J. A review of the mechanism of injury and treatment approaches for illness resulting from exposure to water-damaged buildings, mold, and mycotoxins. Scientific World J. 2013;2013:767482. https://doi.org/ 10.1155/2013/767482. 90. Wild CP, Gong YY. Mycotoxins and human disease: a largely ignored global health issue. Carcinogenesis. 2010;31:71–82. https://doi.org/ 10.1093/carcin/bgp264. 91. Genuis S. Personal Communication. 2017. 92. Rea WJ, Pan Y, Griffiths B. The treatment of patients with mycotoxininduced disease. Toxicol Ind Health. 2009;25:711–714. https://doi.org/ 10.1177/0748233709348281. 93. Diaz DE, et al. Aflatoxin binders II: reduction of aflatoxin M1 in milk by sequestering agents of cows consuming aflatoxin in feed. Mycopathologia. 2004;157:233–241. 94. Gibson NM, Luo TJ, Brenner DW, Shenderova O. Immobilization of mycotoxins on modified nanodiamond substrates. Biointerphases. 2011;6:210–217. https://doi.org/10.1116/1.3672489. 95. Avantaggiato G, Havenaar R, Visconti A. Evaluation of the intestinal absorption of deoxynivalenol and nivalenol by an in vitro gastrointestinal model, and the binding efficacy of activated carbon and other adsorbent

References materials. Food Chem Toxicol. 2004;42:817–824. https://doi.org/ 10.1016/j.fct.2004.01.004. 96. Kerkadi A, et al. Cholestyramine protection against ochratoxin A toxicity: role of ochratoxin A sorption by the resin and bile acid enterohepatic circulation. J Food Prot. 1999;62:1461–1465. 97. Tonstad S, Knudtzon J, Sivertsen M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr. 1996;129:42–49. 98. Alpsoy L, Yildirim A, Agar G. The antioxidant effects of vitamin A, C, and E on aflatoxin B1-induced oxidative stress in human lymphocytes. Toxicol Ind Health. 2009;25:121–127. https://doi.org/10.1177/ 0748233709103413. 99. El-Agamy DS. Comparative effects of curcumin and resveratrol on aflatoxin B(1)-induced liver injury in rats. Arch Toxicol. 2010;84:389–396. https://doi.org/10.1007/s00204-010-0511-2. 100. Praneenararat S. Fungal infection of the colon. Clin Exp Gastroenterol. 2014;7:415–426. https://doi.org/10.2147/CEG.S67776. 101. JU P, et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc. 1999;74:877–884. https://doi.org/10.4065/74.9.877. 102. Shaw W, Kassen E, Chaves E. Assessment of antifungal drug therapy in autism by measurement of suspected microbial metabolites in urine with gas chromatography-mass spectrometry. Clin Pract Alternat Med. 2000;1:15–20. 103. Unpublished Work. Great Plains Laboratory; 2018. 104. Kimura Y, et al. Nematicidal activity of 5-hydroxymethyl-2-furoic acid against plant-parasitic nematodes. Z Naturforsch C. 2007;62:234–238.

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105. Karich A, Kleeberg SB, Ullrich R, Hofrichter M. Enzymatic preparation of 2,5-furandicarboxylic acid (FDCA)-A substitute of terephthalic acid-by the joined action of three fungal enzymes. Microorganisms. 2018;6. https:// doi.org/10.3390/microorganisms6010005. 106. JU P, Sherris DA, Weaver A, Kita H. Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial. J Allergy Clin Immunol. 2005;115:125–131. https:// doi.org/10.1016/j.jaci.2004.09.037. 107. Liang KL, et al. Amphotericin B irrigation for the treatment of chronic rhinosinusitis without nasal polyps: a randomized, placebo-controlled, double-blind study. Am J Rhinol. 2008;22:52–58. https://doi.org/10.2500/ ajr.2008.22.3115. 108. JU P, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2002;110:862–866. 109. Johnson EM, Ojwang JO, Szekely A, Wallace TL, Warnock DW. Comparison of in vitro antifungal activities of free and liposome-encapsulated nystatin with those of four amphotericin B formulations. Antimicrob Agents Chemother. 1998;42:1412–1416. 110. Offner F, et al. Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B. Antimicrob Agents Chemother. 2004;48:4808–4812. https://doi.org/10.1128/AAC.48.12.4808-4812.2004.

139 Sports Nutrition Ralph Esposito, ND, LAc, Jade Teta, ND, and Keoni Teta, ND

OUTLINE Nutrition and Performance, 1035 Performance Nutrition and Fat Loss, 1035 Ketogenic Diet and Athletic Performance, 1035 Intermittent Fasting, 1036 Diet Concerns for Athletes, 1036 Macronutrient Ratios, 1037 Protein, 1037 Fat, 1037 Performance, Recovery, and Nutrient Timing, 1038 Water, 1038 Vitamins and Minerals, 1038 Assessment, 1039 Serum Nutrient Testing, 1039 Adrenal Hormone Testing, 1039 Organic Acid Testing, 1039 Intracellular Nutrient Analysis, 1040 Amino Acid Testing, 1040 Critical Evaluation of Ergogenic Aids, 1040

General Health Concerns for Athletes, 1040 Nutritional Supplements, 1040 Arginine, 1041 Beta-Alanine, 1041 Beta-Hydroxy Beta-Methylbutyrate, 1042 Branched Chain Amino Acids, 1042 Caffeine, 1043 Creatine Monohydrate, 1044 Green Tea Extract, 1045 Quercetin, 1045 Rhodiola, 1045 Sodium Bicarbonate, 1045 Spirulina, 1046 Whey Protein, 1046 Magnesium, 1047 Cold Water Immersion, 1048 Ribose, 1048

Becoming leaner, faster, and stronger, and performing better for longer, all while staying healthy, is the hope of every athlete from the weekend warrior to the elite professional. Sports nutrition is about fueling and enhancing performance, recovering from stress, improving skills quickly, and maintaining optimal body composition for the sport. In this chapter, we will cover the pertinent issues involved in sports nutrition, including supplementation for performance, fitness, muscle maintenance, weight loss, and fat loss.

way to increase training intensity, accelerate recovery, and improve performance. This glycogen dogma has resulted in confusion for athletes and exercise enthusiasts regarding optimal exercise for improving body composition. Health practitioners have known for some time that maximizing glycogen storage increases the performance of endurance athletes. In a 1991 study, Wagenmakers et al.1 showed this effect conclusively. However, this study also showed a direct negative association between glycogen storage and fat burning. Other studies have shown that exercise done in a glycogen-depleted state may have benefits for increasing fat loss.2–4 This information has consequences for athletes and weekend warriors. At times, fat loss is the key aim of an athlete. When this fat loss is the goal, it may be important to tweak the glycogen-centered philosophy of maximizing performance to an approach that instead focuses on fat loss. Health practitioners working with athletes and the general population would be wise to remember the positive association of glycogen with performance and the negative association with fat loss. 

NUTRITION AND PERFORMANCE Performance Nutrition and Fat Loss Before we begin the discussion of sports nutrition, it is useful to cover the topic of body composition. Participating and excelling in sports has much to do with achieving and maintaining an ideal body composition. Athletes seek to optimize the correct ratio of muscle tissue to fat weight that allows the best performance advantage in their sport. More times than not, simply participating in the sport improves body composition. However, when it does not, athletes may, at times, seek to increase muscle mass or decrease their fat weight, or even their overall weight. In addition, the average recreational sport enthusiast, who is not engaged in the competitive side of athletics, will often adopt the eating habits of the elite athletes in the sport they participate in. This practice can be a point of confusion and can lead to undesirable effects. The “glycogen paradigm” is a way of thinking about sports performance that seeks to maximize muscle sugar storage. Some sports nutritionists believe this effort to enhance muscle sugar storage is the best

Ketogenic Diet and Athletic Performance Currently, low-carb diets are the latest trendy diets in the weight loss circles. The one that appears to have the most evidence supporting its use for fat loss as well as some disease states is the Ketogenic diet. This diet is best categorized as a high-fat, moderate-protein, and very lowcarb meal plan, resulting in significant increase in blood ketone levels, sometimes upwards of 4 mmol/L5. Some athletes have implemented the diet to help with athletic performance and weight loss. Although some evidence has been found that the Ketogenic diet can induce

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favorable changes in body composition as well as blood lipid/lipoprotein and glucose levels,6 there is mixed support for its use in improving athletic performance. Daily carbohydrate intake, and to some extent the protein intake, have to be monitored closely so that the body can keto-adapt, typically requiring carbohydrate intake to less than 50 grams daily. By keto-adapting, ketones become the body’s main fuel source over glucose. Once the body keto-adapts or goes into nutritional ketosis, it is forced to start burning fat from the diet and/or from the fat stored in the body via beta-oxidation. High protein intake may make it difficult to put the body into nutritional ketosis, which is due to the gluconeogenic effect of excess protein but also due to the increased supply of oxaloacetate (OAA) from dietary protein, where OAA is the key limiting substrate for the Krebs cycle. Conversely, insufficient protein while in ketosis may affect long-term athletic performance. Furthermore, a keto diet can easily become hypercaloric given the high caloric density of high-fat, low-carbohydrate foods, thus affecting caloric balance and weight loss. This balancing act of hitting the right macronutrient ratio needs to be individualized and carefully monitored; otherwise, it may mean the difference between weight loss and improved performance or fat gain and fatigue. The paucity of studies on the ketogenic diet in terms of ergogenic effects seem to have mixed results, which may explain the limited research. However, some of the research on ketogenic diet and improving athletic performance is intriguing. From a biochemical standpoint, it seems to make sense, at least for endurance athletes, that a more efficient fuel source would be fat instead of carbohydrates. For years, the thought has been that carbohydrate loading for endurance athletes enhances performance. Indeed, some studies support this approach.7 However, some of the research on the ketogenic diet contradicts this notion. Thus far, studies of competitive athletes seem to show that this diet does not adversely affect aerobic endurance8,9 and explosive strength10 and may help with body composition.11–13 However, as yet, there is no consensus on their efficacy in improving performance, and some studies show negative effects of very low-carb diets in athletes.14 

Intermittent Fasting Another intriguing trend that is becoming more prevalent for losing weight, improving health, and enhancing athletic performance among both athletes and the general public is intermittent fasting (IF). Some fitness enthusiasts think IF is a useful tool for losing excess fat weight while simultaneously helping preserve lean body mass.15,16 Shortduration IF of 8 to 48 hours enhances fat burning without causing the rebound weight-gain effects of long-term energy restriction (e.g., the “eat less, exercise more” dogma). Because IF is voluntary as opposed to involuntary fasting (i.e., as in famines, starvation, and long-term dieting), the stress of short-term fasting seems to have significant benefit for the athlete and average person who needs to lose excess weight, the main one being improved compliance. Also, IF and the ketogenic diet seem to potentiate one another in regard to ease of implementation and keto-adapting.17 IF is one way for the average person to lower elevated insulin levels quickly, thus enabling fat burning.18,19 The less insulin in the body, the better one is able to burn fat. Just adding more time without eating between meals over time will help improve insulin sensitivity. Also, high insulin levels tend to cause the kidneys to retain sodium, and thus result in water retention. Becoming more insulin sensitive helps the body shed excess water, which is one of the first signs that a person is less resistant to insulin and that fat burning is beginning to happen. There are many myths about IF that are not borne out in the research, because many of the studies are done on complete fasting (some with individuals who were even foregoing water) and long-term

caloric restriction. IF is very different physiologically from starvation or long-term energy deficient states. Some of the more common misconceptions are the following: • IF causes muscle loss. • IF causes fatigue, irritability, and low energy. • IF causes athletic performance to suffer. Although it may be true that fasting more than 24 hours can cause athletic performance to be compromised in some individuals, and much longer fasts (longer than 72 hours) can cause muscle loss and poor mood, IF for less than 24 hours typically will not have such results and may even improve performance, depending on the sport. In addition, the notion that short-term fasting causes muscle loss or fat gain, or low energy, poor moods, and compromised focus simply is, as of yet, unfounded. In fact, the opposite may be true.20 From an ancient ancestral perspective, our species endured numerous periods of feast and famine. If they had not adapted to that forced intermittent fasting, our species, as we know it, would not have survived. Those experiences primed our ancient ancestors and us to preserve our muscle mass and brain function during times of food scarcity so that we would have the energy level and focus to find food. This process occurs because the body has an alternative fuel source like ketones, which result from burning fat. Keto-adaptation (nutritional ketosis) helps preserve muscle mass, energy levels, and brain function so that food can be pursued and found.21 If the famine continues too long, then starvation ketosis sets in, and muscle mass, energy levels, and eventually focus suffer. The benefits of IF over conventional weight loss recommendations are that it seems to increase compliance,22 improve health,23 and possibly improve performance24 and mental focus.25 Much more study is needed, but thus far, IF seems to have many health benefits over longterm energy restriction for fat loss and may improve athletes’ performance if done intermittently for short periods of time while ensuring the unique needs of the athlete are met. 

Diet Concerns for Athletes Nutrition for exercise performance involves fueling the body for performance. This process requires optimal energy resources to make up for caloric expenditure during exercise. Athletic activities can use significant resources. High-intensity daily exercise can burn from 600 to 1200 calories/day.26–28 Elite athletes, such as professional cyclists, can burn as many as 12,000 calories/day, necessitating a large compensatory calorie intake. Caloric needs this high can be extremely difficult to obtain through “real” food alone.26–31 This difficulty makes supplementation of functional foods and supplements necessary for athletes undergoing heavy training. Health care providers advising athletes on nutrition must take many factors into account. In addition to the caloric issues just described, there are several other issues. Many athletes undergoing the intense stress of training can experience loss of appetite, especially after intense exercise.32 Athletes are often also under the constraints of tight schedules of competition and travel requirements, which can prevent or interrupt scheduled meals. Given the already tight training schedules, athletes can quickly become overwhelmed by food considerations. Another potential problem may be lack of variety in the diet, which can lead to lack of enjoyment in eating and loss of appetite. To address these issues, athletes engaged in heavy training should work to ensure muscle is not lost and weight is maintained, which means eating calorie-dense meals and snacks that are convenient for an athlete’s lifestyle. Although real and whole foods should be emphasized, the use of protein bars, meal-replacement shakes, electrolyte beverages, and nutritional vitamin and mineral supplements will often be needed. Ideally, athletes involved in intense training should eat

CHAPTER 139  between four and six meals per day and should eat in consistently timed intervals. Meal and snack timing around training is also an important consideration to replenish energy and aid recovery.32 Athletes should understand that without calorie balance, many supportive training aids will not provide much advantage. Maintaining caloric needs is the foundation on which all other ergogenic aids should be built. 

Macronutrient Ratios In addition to the caloric considerations of athletes, balancing the protein, fat, and carbohydrate ratio is also important. Recreationally active individuals are usually advised to consume from 45% to 55% carbohydrates, 10% to 15% protein, and 25% to 35% fat.26–28 The macronutrient needs of athletes can far exceed these numbers. Carbohydrate requirements for athletes can increase up to 10% to replenish and maximize liver and muscle glycogen storage.27,28 These carbohydrates should come from low-glycemic-index sources that do not cause rapid fluctuations in blood glucose. Because higher levels of complex, low-glycemic carbohydrates can be hard to consume, fruit juices, energy bars, and other convenience foods may be considered. Research related to carbohydrate intake in athletes shows that athletes may reach what is called a “carbohydrate tipping point.”27 This point is a level of carbohydrate beyond which there ceases to be a performance advantage. Research suggests the body can burn 1 to 1.1 g of carbohydrate per minute, amounting to roughly 60 g of carbohydrate per hour of exercise.27 Harger-Domitrovich et al.33 showed approximately 50 g of carbohydrate for a 165-lb individual was the optimal intake of carbohydrates for athletes. This intake amounts to 0.27 g of carbohydrate needed per pound of body weight each hour during exercise. It is also interesting to note that not all carbohydrates are created equal. Research suggests that sugars composed mainly of glucose (maltose, maltodextrin, and other polysaccharides) are burned at a higher rate in comparison with nonglucose sugar (fructose, galactose, etc.). The combination of these sugars seems to be most advantageous.27 Evaluating carbohydrate sources on the relative ratios of these sugars may be wise. The glucose/fructose ratio of close to 1:1 seems optimal. 

Protein Protein is an essential nutrient for all humans but especially so for athletes. Recent research on protein intake has shown that athletes require two times or more of the reference daily intake.27,34–39 It is now recommended that athletes involved in very high-volume training catabolize between 0.7 and 0.9 g of protein per pound of body weight per day. This amounts to between 115 and 150 g of protein per day for a 165lb athlete. Lean proteins sources such as chicken breast, fish, and lean meats provide approximately 25 g of protein per 3-oz serving; therefore athletes benefit most from consuming approximately 5 to 7 oz of these lean protein sources per day. This amount would be the equivalent of about five to seven 3-oz servings of chicken, fish, or other lean protein per day, with the assumption of fats and carbohydrates to be negligible in lean protein sources. Protein considerations are especially important for endurance athletes, who are more susceptible to protein malnutrition due to the catabolic hormonal environment created by their sport.39–41 Like carbohydrates, not all protein is the same. The amino acid content of protein sources varies and has direct bearing on quality. Different types of protein can be described as fast proteins or slow proteins.42,43 Slow proteins are digested more evenly and take longer to process. Fast proteins are digested more rapidly and allow amino acids to be quickly available to the body. The typical fast- and slow-protein sources are whey and casein, respectively. Health care providers working with athletes may want to look at slow proteins as good meal options, whereas fast

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protein may be great options to aid performance and recovery by timing them for intake before and after exercise. The best sources of protein are low fat and have a high biological value with optimal amino acid ratios. These sources include skinless chicken, lean beef, fish, egg whites, skim milk, lean pork, and the supplemental milk proteins casein and whey. The International Society of Sports Nutrition published its position on protein intake in 2017, highlighting the following points44,45: 1. Highly active individuals should consume between 1.4 and 2 g of protein per kilogram of body weight. 2. Higher protein intakes (2.3–3.1 g/kg/day) may be needed to maintain lean body mass in resistance-trained athletes following a hypocaloric regime. 3.  Concern that protein intake within this range is unhealthy is unfounded. 4. Attempts should be made to get protein from whole foods, but supplemental protein is a safe and viable method of protein intake. 5. Timing protein intake before and after exercise may have benefits, including enhanced recovery and development of muscle mass. 6. Certain amino acids, such as leucine, a branched chain amino acid (BCAA), have been shown to be beneficial for increasing the rate of protein synthesis, decreasing protein breakdown, and increasing recovery from exercise.46 Exercising individuals require more protein than their sedentary counterparts require. 

Fat Fat intake for athletes involves several important considerations and depends on an athlete’s goals and training state. In general, athletes’ fat recommendations should be at or slightly greater than those for their nonathlete sedentary counterparts.27,34 High-volume athletic training has been shown to lower testosterone concentrations, and decreasing fat intake can exacerbate this effect.47–49 Most research suggests athletes should keep their dietary fat intake at around 30% of total calories. However, ultraendurance athletes, in particular, may go much higher than this. Athletes undergoing very intense training regimes have been shown to safely tolerate and benefit from diets containing as much as 50% of total calories from fat.50 As mentioned previously, weight loss is occasionally a concern for athletes. In those cases, a lower-fat diet may be advisable, with research suggesting a diet of 0.25 to 0.5 g of fat per pound per day.51 Fat quality is also a concern. The polyunsaturated fatty acid ratio of ω-6/ω-3 may be a concern in immune system function and inflammatory responses. Saturated fat intake may also be associated with more optimal testosterone responses.49 Given these considerations of fat and the emerging understanding of the different function of fats, it is wise for athletes to consume a wide range of dietary fats, with a special focus on balancing the ω-3/ω-6 ratio. 

Improving Athletic Performance with Nutrition International Society of Sports Nutrition position stand: nutrient timing 2010 Prolonged exercise (>60–90 min) of moderate-to high-intensity exercise will deplete the internal stores of energy, & prudent timing of nutrient delivery can help offset these changes. During intense exercise, regular consumption (10–15 fl oz.) of a carbohydrate/electrolyte solution delivering 6%–8% CHO (6–8 g CHO/100 ml fluid) should be consumed every 15–20 minutes to sustain blood glucose levels. Glucose, fructose, sucrose, and other high-glycemic CHO sources are easily digested, but fructose consumption should be minimized as it is absorbed at a slower rate and increases the likelihood of gastrointestinal problems. Continued

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Improving Athletic Performance with Nutrition—cont’d The addition of PRO (0.15–0.25 g PRO/kg/day) to CHO at all time points, especially post-exercise, is well tolerated and may promote greater restoration of muscle glycogen when carbohydrate intakes are suboptimal. Ingestion of 6–20 gms of essential amino acids and 30–40 gms of highglycemic CHO within 3 hours after an exercise bout and immediately before exercise has been shown to significantly stimulate muscle PRO synthesis. Daily post-exercise ingestion of a CHO plus PRO supplement promotes greater increases in strength and improvements in lean tissue and body fat percentage during regular resistance training. Milk PRO sources (e.g., whey and casein) exhibit different kinetic digestion patterns and may subsequently differ in their support of training adaptations. Addition of creatine monohydrate to a CHO plus PRO supplement in conjunction with regular resistance training facilitates greater improvements in strength and body composition as compared with when no creatine is consumed. Dietary focus should center on adequate availability and delivery of CHO and PRO. Including small amounts of fat does not appear to be harmful and may help to control glycemic responses during exercise. Irrespective of timing, regular ingestion of snacks or meals providing both CHO and PRO (3:1 CHO: PRO ratio) helps to promote recovery and replenishment of muscle glycogen when lesser amounts of CHO are consumed. CHO, Carbohydrate; PRO, Protein. From Kerksick CM, Arent S, Schoenfeld BJ, et al. International society of sports nutrition position stand: nutrient timing. J Int Soc Sports Nutr. 2017;14:33. https://doi.org/10.1186/s12970-017-0189-4.

Performance, Recovery, and Nutrient Timing Athletes and those working with them can benefit greatly from understanding how to time meals for performance and recovery. When it comes to performance nutrition, it is useful to think about first maximizing storage capacity (i.e., filling the liver and muscle glycogen stores) and fueling exercise (i.e., having nutrients more recently consumed to fuel exercise).26–28,46 Complex carbohydrates take about 4 to 6 hours to be digested, absorbed, and then stored in the liver and muscle as glycogen.26–28,46,52 Recommendations regarding carbohydrate loading for training and competition should take that time into account. Morning training sessions or competition will benefit from nighttime loading strategies, whereas afternoon competition and training sessions will benefit from morning loading strategies. A light carbohydrate and protein shake roughly 45 minutes (30–60 minutes) before activity has been shown to improve performance toward the end of high-intensity activity. The inclusion of protein also serves to spare muscle tissue by decreasing the need for the body to cannibalize its own muscle tissue.53,54 Although exercise sessions of less than an hour require no special nutritional or hydration strategies, exercise sessions lasting longer do. Strategies that manage pre-, post-, and within-workout nutritional requirements can dramatically aid performance and recovery. This is where electrolyte solutions and sports drinks consumed before and during exercise have an important role to play. These beverages can help prevent low blood sugar, optimize hydration, replace lost minerals, and reduce the immune suppression that occurs after intense long-duration exercise.55,56 A carbohydrate beverage of 6% to 8% with an equal mixture of glucose and fructose taken every 20 minutes during exercise is advised.27,54,57 In addition, adding protein to carbohydrate intake may result in higher rates of glycogen storage after exercise.32,55,57,58 Research suggests consumption of approximately 20 g of a rich source of essential amino acids (e.g., whey protein) combined with 40 g of a good glucose source (e.g., grape juice) taken 40 minutes before exercise may be useful and within 3 hours after exercise

may improve performance and aid recovery. The addition of a small amount of fat may also be helpful in stabilizing blood glucose levels.57 After exercise, there is a unique opportunity to fuel the body for recovery. During this “recovery phase,” nutritional strategies should be instituted as soon as possible and at least within the first 30 minutes after the cessation of exercise. A mixed carbohydrate–protein beverage containing close to a 3:1 ratio of carbohydrate to protein within 3 hours after exercise appears to provide greater recovery benefits than do lesser amounts of carbohydrate.32,55,57–59 Upon completion of this postworkout “snack,” another more carbohydrate-heavy postworkout meal should be eaten again within 90 minutes. Most athletes will taper their training by one third to one half 2 to 5 days before their events. During that time, it may be beneficial to consume 200 to 300 extra grams of carbohydrates daily. This technique has been shown to maximize glycogen storage before the event and improve performance.57 

Water Easily the most beneficial ergogenic aid is water. Working to prevent dehydration during exercise is one of the most useful endeavors for improving exercise performance. Intense exercise can result in significant loss of water through sweat. When this fluid is not replaced, athletic performance will suffer. A loss of 2% water through sweat can impair the ability to compete, and a loss of 4% can result in the inability of the body to cool itself during exercise.56 Athletes can lose 1 to 2 L in sweat through exercise per hour. Unfortunately, athletes cannot rely on thirst perception to regulate fluid balance.56 There are several objective ways for athletes to measure fluid loss.56 One way to ensure adequate hydration recovery is for athletes to weigh themselves before and after exercise and drink 3 cups of liquids per pound of weight lost through exercise. During heavy exercise, athletes should consume 1 to 2 L of water or glucose and/or electrolyte beverage per hour.56,60 

Vitamins and Minerals It is now recommended by most medical organizations that a low-dose multivitamin be consumed daily to assure optimal vitamin and mineral status.27,61 Few, if any, vitamins and minerals have been shown conclusively in research to have any performance benefit. However, the nutritional status of an athlete can affect quality of performance, training, and recovery.27,61–64 When considering vitamin and mineral supplementation for athletes, health care practitioners should view their recommendations in the context of nutrient adequacy. Athletes may be more susceptible to vitamin and mineral inadequacies, given the previously mentioned issues on nutrition and potential caloric deficits. Although there may be no direct benefits to performance, many vitamins and minerals aid recovery and support.27,61–64 Vitamin C and zinc in particular have good research suggesting immune enhancement during intense training periods.27 Vitamins C and E, along with other antioxidant nutrients, may also protect athletes from excessive oxidative damage, which could also lead to immune suppression.27 Mineral deficiencies are particularly problematic for athletes. Restoring any mineral deficiencies can aid performance.27 Certain minerals may also provide benefit for optimizing performance. Calcium is one mineral that can aid athletes. Although there is no evidence that calcium supplementation improves performance, at supplement levels of approximately 1000 mg per day, calcium has been shown to assist athletes susceptible to osteoporosis as well as improve body composition.65,66 Phosphorus supplementation may have ergogenic effects when supplemented as sodium phosphate but not in other forms (calcium phosphate, potassium phosphate, etc.).67 Levels of supplementation for phosphate are 4000 mg/day (1 g tribasic

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dodecahydrate sodium phosphate 4 times/day) for 3 days for endurance improvement. Sodium intake has benefit for training in the heat and reduces the risk of hyponatremia.48 With most minerals, as with vitamins, the real benefit to athletes comes when identified deficiencies are corrected. Restoring vitamin and mineral status to optimal levels can aid exercise performance.7,41-44 Along these lines, vitamin D is a special consideration. Vitamin D deficiency is now epidemic, and athletes have the same rates of deficiency as the rest of the public have.68,69 In one study of elite female gymnasts, 77% were found to have vitamin D levels lower than 35 ng/ mL, and a full third had levels lower than 10 ng/mL (which is defined as a clinical deficiency).69 In a group of athletes susceptible to prolonged and constant bone stress (i.e., long-distance runners), this finding was especially troubling and underscores the need for athletes to ensure adequate vitamin D status. Although vitamin D supplementation in individuals with sufficient vitamin D does not appear to increase performance, vitamin D therapy delivered to deficient athletes may improve performance.69,70 Vitamin D is known for its role in bone metabolism. However, the fact that skeletal muscle has vitamin D receptors is not commonly known. As far back as the 1930s, there have been numerous reports of the beneficial effects of ultraviolet therapy on athletic performance.71,72 In addition, some studies suggest the season of training makes a difference. One of these studies showed that training in the summer months creates greater gains than the same volume of training in autumn or winter does, despite the same stimulus.72 In both older and younger individuals, adequate vitamin D status affects neuromuscular function and may have a specific relationship to the maintenance of the fast-twitch type 2 muscle fibers.68,71,73,74 In a study on teenage athletes, vitamin D deficiency lowered muscle power and force.75 Vitamin D levels are also related to myalgia, fatigue, and reduced motivation to exercise. Studies in older adults showed that levels of vitamin D were correlated with the propensity to fall.76 A meta-analysis of vitamin D levels showed a 20% reduction in the risk of falling among people with higher levels.77 This reduction was likely due to vitamin D’s ability to improve reaction speed, balance, and neuromuscular performance. Much of this effect may be explained by the ability of vitamin D to help maintain and even build type 2 muscle fibers. Athletes should be tested for vitamin D levels with a serum 25-hydroxy vitamin D laboratory test with a target between 50 and 100 ng/mL. If they are found to be insufficient, a combination of supplementation and sun exposure is advisable. For quick restoration of adequate vitamin D levels, 50,000 International Units (IUs) of vitamin D per week for 12 weeks has been shown to allay symptoms of vitamin D deficiency. Maintenance doses of between 1000 and 10,000 IU/day, depending on sun exposure and living latitude, should also be considered to prevent subclinical and clinical deficiencies. 

their textbook Laboratory Evaluations for Integrative and Functional Medicine, “For various reasons specific to each vitamin, it is possible for an individual to have normal serum levels of a vitamin while exhibiting signs of insufficiency for that vitamin owing to a lack of adequate intracellular concentration to meet the metabolic demands of the cells.”78 Given these factors, serum may not always be the best means of determining nutritional status for all nutrients. A range of laboratory analyses that can provide more functional assessments of nutrition status are now available.78 The ones that may be most beneficial are adrenal hormone profiles (cortisol and dehydroepiandrosterone [DHEA]), organic acid testing, and intracellular nutrient analysis. 

ASSESSMENT

Organic Acid Testing

Serum Nutrient Testing Nutrient deficiencies can affect many aspects of physical performance, recovery, and immune function. Athletes, because of the imposed increases in metabolism, can be at an increased risk for nutrient deficiencies. Serum testing is a reliable and useful tool for diagnosis of severe nutrient deficiencies but may be inadequate for certain vitamins and minerals.78 Therefore those working with athletes will find it useful to have more functional tools for assessment of metabolic and nutritional needs. Testing blood for nutritional levels can be misleading. Serum nutrient concentrations are closely regulated by the body and can fluctuate based on recent intake. Furthermore, some vitamins and minerals are almost entirely found intracellularly. As stated by Lord and Bralley in

Adrenal Hormone Testing Analyzing the adrenal hormones cortisol and DHEA can give insight into training status and into whether an athlete may be overtraining or overreaching.79–81 Salivary cortisol and DHEA levels provide an indication of catabolic versus anabolic balance in the body as well as neuroendocrine adaptation to stress. The optimal ratio of salivary cortisol to DHEA is approximately 5:1 to 6:1, which indicates an appropriate state of stress adaptation. The closer this ratio is to 1:1, the less likely it is for the individual to be able to adapt to daily stressors.82 The test is simple and noninvasive, involving salivary collection at four time points during the day (morning, noon, evening, and night). Depending on the laboratory, the cortisol and DHEA test may also provide markers of immune function, such as immunoglobulin-A. All these measures are important for athletes looking to compete at high levels for prolonged periods. The body goes through four stages in response to stress. Stage 1 occurs in response to acute stress and involves elevations in cortisol with no changes in DHEA. Stage 2 involves continued stress and is marked by a sustained cortisol peak with a matching elevation of DHEA. At stage 3, when stress continues and becomes chronic, cortisol levels drop, whereas DHEA stays high. Finally, both cortisol and DHEA fall, a stage often referred to as adrenal exhaustion or stage 4. Testing athletes for levels of adrenal hormones gives important guidance concerning nutritional therapy and supplementation. Cortisol is a highly catabolic agent, and increased cortisol levels with normal to low DHEA indicate excessive stress and potential muscle wasting.78 This status necessitates increased protein and amino acid intake, especially increased glutamine.83 High cortisol levels also give an indication of increased need for other nutrients that are easily depleted through increased metabolic activity (e.g., magnesium, zinc, and vitamin B6).78 Cortisol-suppressing supplements, such as phosphatidylserine, may also be indicated,84 as is the potential for DHEA supplementation and/or immune support.85 Changes in adrenal hormones may occur long before clinical symptoms appear and can be used to monitor training status and recovery. 

Organic acid testing is a useful analysis that looks at metabolic by-products in urine.78 The test does not measure actual vitamins and minerals or their absolute values but assesses them indirectly by measuring excreted metabolic by-products. Although the test is not diagnostic, it can be used to analyze the metabolic consequences of insufficient nutrient intake. It can also offer insights into toxic exposures, digestive health, amino acid need, and neuroendocrine function. Fats, proteins, and carbohydrates become carboxylic acids before they are completely burned to carbon dioxide. These acids, formed by the body’s metabolic processes, are usually low or nonexistent in urine. When perturbations occur in metabolism due to inefficient enzymes as a result of genetic polymorphisms and/or lack of a vitamin or mineral cofactor, the metabolic by-products can build up in the cell, be

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released into the blood, and then begin to show up in the urine. The organic acids that appear can then be traced back to known biochemical pathways, indicating a particular nutrient need. Given the fact that almost all nutrients become ergogenic when there is a deficiency or increased need, organic acid testing may be useful in understanding which nutrients may be indicated for a particular athlete and whether the supplements they are currently taking are actually doing the job. Using organic acid testing may provide health care practitioners working with athletes a way to pinpoint potential nutrient issues and bolster key metabolic pathways. 

Intracellular Nutrient Analysis Because many nutrients, like magnesium, are not well measured in serum, another useful functional analysis for athletes is intracellular nutrient analysis.78 This testing involves drawing blood, isolating white blood cells, and growing them in a nutrient-rich medium. Individual nutrient concentrations are then manipulated one by one while measuring cell growth rates. Cellular growth from an athlete with insufficient levels of a nutrient will be slower than from an athlete with sufficient levels.86 This analysis allows tailored nutrient supplementation to optimize intracellular levels of all nutrients. 

Amino Acid Testing Due to the high turnover of amino acids required in the participation and recovery from intense exercise, amino acid analysis can be useful for athletes.78,87 When testing athletes for amino acids, it may be useful to measure plasma levels, urine levels, and organic acids. Plasma levels give the best indication of protein utilization and are the most scientifically validated. However, urinary amino acids may give greater insight into protein breakdown from factors interfering with amino acid utilization (i.e., micronutrient deficiency or toxic exposures). These two measures, along with the ability to map biochemical pathways through organic acid testing, can provide an athlete with in-depth information about protein utilization, breakdown, and metabolic needs. 

CRITICAL EVALUATION OF ERGOGENIC AIDS It is important for the health care practitioner to be aware of the large gap that often exists between supplement marketing and research. Given that nutritional supplements are not regulated to the same degree as pharmaceuticals, and little financial incentive exists to research natural compounds, it is important to look for valid and objective resources on nutritional supplements. When evaluating whether a nutraceutical might be useful, it is important to keep several things in mind.27 A good first question to ask is, “Does the basic science make sense?” Natural health practitioners need to be good students of biochemistry and physiology. Knowing the compound and its involvement in biochemical pathways is a necessary first step. If the mechanism of action “makes sense” from a biochemical perspective, the supplemental aid may have merit. A good example here is the use of the nutrient l-carnitine. Understanding the biochemistry of this nutrient as key in delivering fat to the mitochondria to be burned for energy allows consideration that it may have fat loss and performance benefits. The next question must be, “Is it feasible to deliver the nutrient in a form that can actually be absorbed and utilized by the body?” Although a nutrient may seem like a perfect candidate for performance enhancement properties, if it cannot be delivered to the body in a safe, feasible, and usable form, it will not have much use. In the case of l-carnitine, several issues warrant consideration. First, l-carnitine is not well absorbed; therefore understanding the different delivery forms is essential. The next obvious question, “Would l-carnitine

bound to tartrate, fumarate, or another molecule be most feasible for delivery?” Also, in the case of amino acids like carnitine, there are two forms, l-carnitine and d-carnitine. l-carnitine is active in the body, whereas d-carnitine is not and can actually block the action of l-carnitine. Confidence would therefore be less on studies using the racemic mixture of this nutrient versus those using pure l-carnitine. Another important consideration is, “Does any good research exist on the substance?” Health care practitioners should further consider other aspects: Are the studies in vitro or in vivo studies? Were they animal or human studies? Was the sample size big enough? Was the study designed appropriately? Was it well controlled? Human clinical trials with a large sample size that are double-blinded and placebo-controlled are obviously the gold standard and should be weighted heavier. However, these types of studies often do not exist for sports performance supplements, accounting for much of the skepticism regarding sports performance aids. Moreover, these types of studies are cost-prohibitive, especially when considering the diminutive financial gain, if any at all, of doing natural compound studies because there is essentially no patent protection. Much of this skepticism is warranted, although discounting a supplement purely on the basis of lack of these types of trials is probably not wise. Some final considerations would be whether or not the product is safe, legal, and appropriate. In 2006 the 109th Congress passed the Dietary Supplement and Nonprescription Drug Consumer Act. This law requires supplement companies to disclose all complaints about their products and make them available to the public. For supplement issues that are more serious in nature, the companies must notify the U.S. Food and Drug Administration within a 2-week time frame. There are also consumer organizations that help police the industry. These organizations independently test supplement products against claims of efficacy and issues with contamination, and such groups can be useful resources to those advising supplement use. Finally, there are always completely safe products that may present issues in certain populations. All these considerations should be evaluated when using nutritional supplementation. 

GENERAL HEALTH CONCERNS FOR ATHLETES The American Medical Association has suggested Americans use supplemental vitamins to maintain health; these recommendations seem especially prudent in the athletic world. Although there is no performance benefit to the use of multiple vitamins and minerals, as discussed previously, athletes can be susceptible to deficiencies and/or require more support in areas due to increased vulnerability to stress or injuries encountered during sports. Glucosamine can aid in the healing of damaged cartilage and reduce joint pain.69 Supplements such as zinc, glutamine, vitamin C, lipoic acid, selenium, and other nutrients may support immune function and antioxidant capacity.26,27,46,88–90 Amino acids are especially useful. Creatine, whey protein, BCAAs, and l-carnitine tartrate have all been shown to help athletes through the stress of intense training periods.26,27,46 Finally, ω-3 fats can help balance inflammatory and anti-inflammatory reactions in the body. 

NUTRITIONAL SUPPLEMENTS Obviously, a full treatment of all the nutraceuticals purported to have beneficial effects in exercise and body composition could fill an entire book. We selected the compounds discussed here that demonstrated the most research supporting their use as ergogenic aids. We attempted to avoid looking at compounds that have strong theoretical support for their use but have not yet been studied. We gave special consideration to compounds that have been studied in humans and have been

CHAPTER 139  evaluated under double-blinded and placebo-controlled conditions. Newer compounds that did not meet these criteria may not be covered. In certain cases, we included compounds that are novel in their reported use as ergogenic substances.

Arginine Arginine has several potential benefits for athletes, including increasing human growth hormone production, blood flow, mitochondrial biogenesis, fat loss, and muscle gain. Many of these effects are related to nitric oxide, for which arginine is a precursor. However, several of these benefits are relatively new discoveries regarding arginine supplementation. Animal studies and human studies show arginine might have particular benefit in improving exercise capacity and body composition. Arginine may play a role in endurance performance. A 2010 study showed that a proprietary arginine supplement given to elderly male cyclists was able to positively affect performance. The arginine supplement significantly increased the anaerobic threshold within 1 week of beginning supplementation, with the effect lasting throughout the 3-week study.91 No change in maximal oxygen consumption (VO2max) among the cyclists was found in this particular study. However, in another study, this time on younger cyclists, oxygen kinetics were sped up in relation to l-arginine supplementation.92 Another study in 2010 showed arginine’s potential role in illness associated with reduced cardiovascular capacity.93 In this analysis, arginine supplementation improved exercise capacity in heart transplantation patients, resulting in furthering the distance walked and delaying the ventilatory threshold by 1.2 minutes. In addition to endurance benefits, arginine may also have a role to play in strength training. An April 2010 study showed increased growth hormone and insulin-like growth factor 1 release in response to heavy resistance training.94 This newer study lends credibility to older reports. Research on rats, pigs, and humans showed arginine to be a potential antiobesity aid through several unique mechanisms.95 Supplemental arginine appears to have activity that increases glucose and long-chain fatty acid oxidation while at the same time suppressing gluconeogenesis and lipogenesis. In rats, l-arginine was shown to increase muscle mass by 12% and increase glucose metabolism by 14% without affecting insulin. Most interestingly, arginine was shown to coax white adipose tissue to become brown adipose tissue and, as a result, significantly elevated the metabolic rate. Arginine appears to act partly via its conversion to nitric oxide. It may act via cyclic guanosine monophosphate and cyclic adenosine monophosphate dependent mechanisms. It was found to increase mitochondrial biogenesis, upregulate GLUT-4 receptors, and improve muscle mass. A 21-day randomized and double-blind, placebo-controlled study of arginine in obese men was conducted in 2006 by Lucotti et al.96 Thirty-three obese males were put on a low-calorie diet (1000 kcal/ day) and an exercise program (45 minutes of exercise twice per day for 5 days/week). They were then randomized to receive 8.3 g per day of arginine or placebo. As expected, the lifestyle intervention resulted in weight loss, waist circumference reduction, lowered fasting glucose, and reduced insulin in both groups. However, the arginine group had statistically better responses in most measures in comparison with the placebo group (P T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618–626. 203. Brocardo PS, Budni J, Lobato KR, Santos AR, Rodrigues AL. Evidence for the involvement of the opioid system in the antidepressant-like effect of folic acid in the mouse forced swimming test. Behav Brain Res. 2009;200(1):122–127. 204. Einat H, Clenet F, Shaldubina A, Belmaker RH, Bourin M. The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors. Behav Brain Res. 2001;118(1):77–83. 205. Brink CB, Viljoen SL, de Kock SE, Stein DJ, Harvey BH. Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. Metab Brain Dis. 2004;19(1–2):51–70. 206. Mukai T, Kishi T, Matsuda Y, Iwata N. A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol. 2014;29(1):55– 63. https://doi.org/10.1002/hup.2369. 207. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001;21(3):335–359. 208. Jensen JE, Daniels M, Haws C, et al. Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp Clin Psychopharmacol. 2008;16(3):199–206. 209. Attenburrow MJ, Odontiadis J, Murray BJ, et al. Chromium treatment decreases the sensitivity of 5HT2A receptors. Psychopharmacology. 2002;159:432–436.

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235. Güzelcan Y, Scholte WF, Assies J, Becker HE. Mania during the use of a combination preparation with St.John’s wort (Hypericum perforatum). Ned Tijdschr Geneeskd. 2001;145(40):1943–1945. 236. Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol. 2019;71(1):129–138. https:// doi.org/10.1111/jphp.12858. Epub 2018; Feb 7. 237. Muthuramalingam A, Menon V, Rajkumar RP, Negi VS. Is depression an inflammatory disease? Findings from a cross-sectional study at a tertiary care center. Indian J Psychol Med. 2016;38(2):114–119. 238. Glaus J, von Känel R, Lasserre AM, et al. Mood disorders and circulating levels of inflammatory markers in a longitudinal population-based study. Psychol Med. 2018;48(6):961–973. https://doi.org/10.1017/ S0033291717002744. Epub 2017; Sep 20. 239. Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J Am Med Dir Assoc. 2017;18(6):503–508. https://doi.org/10.1016/j.jamda.2016.12.071. Epub 2017; Feb 22. 240. Brietzke E, Mansur RB, Zugman A, et al. Is there a role for curcumin in the treatment of bipolar disorder? Med Hypotheses. 2013;80(5):606–612. https://doi.org/10.1016/j.mehy.2013.02.001. Epub 2013 Feb 26. 241. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. 242. O’Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173(12):1899–1910. 243. Beale C, Broyd SJ, Chye Y, et al. Prolonged cannabidiol treatment effects on hippocampal subfield volumes in current cannabis users. Cannabis Cannabinoid Res. 2018;3, No. 1. Published Online:1. 244. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–130. 245. Cannabidiol as an adjunctive treatment for bipolar depression (CBDBD). https://clinicaltrials.gov/ct2/show/NCT03310593. Accessed January 26, 2019. 246. Zhao X, Wang C, Zhang JF, et al. Chronic curcumin treatment normalizes depression-like behaviors in mice with mononeuropathy: involvement of supraspinal serotonergic system and GABAA receptor. Psychopharmacology (Berl). 2014 May;231(10):2171–2187. https://doi.org/10.1007/ s00213-013-3368-2. Epub 2013 Dec 3. 247. Miyasaka LS, Atallah AN, Soares BG. Passiflora for anxiety disorder. Cochrane Database Syst Rev. 2007;1:CD004518. 248. Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine. 2010;17(7):481–493. https://doi.org/10.1016/j.phymed.2010.02.002. 249. Mao JJ, Xie SX, Zee J, et al. Rhodiola rosea versus sertraline for major depressive disorder: a randomized placebo-controlled trial. Phytomedicine. 2015;22(3):394–399. 250. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47–53. 251. Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014;29(6):517–527. https://doi.org/10.1002/hup.2434. 252. Tóth B, Hegyi P, Lantos T, et al. The efficacy of saffron in the treatment of mild to moderate depression: a meta-analysis. Planta Med. 2019;85(1):24–31. https://doi.org/10.1055/a-0660-9565. 253. Modabbernia A, Sohrabi H, Nasehi AA, et al. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). 2012;223(4):381–388. 254. Kashani L, Raisi F, Saroukhani S, et al. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol. 2013;28(1):54–60. https://doi.org/10.1002/hup.2282. 255. Maleki-Saghooni N, Mirzaeii K, Hosseinzadeh H, Sadeghi R, Irani M. A systematic review and meta-analysis of clinical trials on saffron (Crocus sativus) effectiveness and safety on erectile dysfunction and semen parameters. Avicenna J Phytomed. 2018;8(3):198–209.

256. Pilkington K, Kirkwood G, Rampes H, Fisher P, Richardson J. Homeopathy for depression: a systematic review of the research evidence. Homeopathy. 2005;94(3):153–163. 257. Grimaldi-Bensouda L, Abenhaim L, Massol J, et al. Homeopathic medical practice for anxiety and depression in primary care: the EPI3 cohort study. BMC Complement Altern Med. 2016;16:125. https://doi .org/10.1186/s12906-016-1104-2. 258. Davidson JR, Crawford C, Ives JA, Jonas WB. Homeopathic treatments in psychiatry: a systematic review of randomized placebo-controlled studies. J Clin Psychiatry. 2011;72(6):795–805. https://doi.org/10.4088/ JCP.10r06580. 259. Dwivedi T, Zhang H. Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Front Neurosci. 2015;8:457. https://doi.org/10.3389/fnins.2014.00457. 260. Little HR, Kramer JM, Beatty JA, Waldrop TG. Chronic exercise increases GAD gene expression in the caudal hypothalamus of spontaneously hypertensive rats. Brain Res Mol Brain Res. 2001;95(1–2):48–54. 261. Ota M, Wakabayashi C, Sato N, et al. Effect of L-theanine on glutamatergic function in patients with schizophrenia. Acta Neuropsychiatr. 2015;27(5):291–296. https://doi.org/10.1017/neu.2015.22. 262. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206–215. 263. Gong P, Fan H, Liu J, Yang X, Zhang K, Zhou X. Revisiting the impact of OXTR rs53576 on empathy: a population-based study and a meta-analysis. Psychoneuroendocrinology. 2017;80:131–136. https://doi .org/10.1016/j.psyneuen.2017.03.005. 264. Morhenn V, Beavin LE, Zak PJ. Massage increases oxytocin and reduces adrenocorticotropin hormone in humans. Altern Ther Health Med. 2012;18(6):11–18. 265. Cui SS, Bowen RC, Gu GB, Hannesson DK, Yu PH, Zhang X. Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J Neurosci. 2001;21(24):9867–9876. 266. Petrilli MA, Kranz TM, Kleinhaus K, et al. The emerging role for zinc in depression and psychosis. Front Pharmacol. 2017;8:414. https://doi .org/10.3389/fphar.2017.00414. 267. Tao S, Chattun MR, Yan R, et al. TPH-2 gene polymorphism in major depressive disorder patients with early-wakening symptom. Front Neurosci. 2018;12:827. https://doi.org/10.3389/fnins.2018.00827. 268. Pfeffer CR, Altemus M, Heo M, Jiang H. Salivary cortisol and psychopathology in children bereaved by the September 11, 2001 terror attacks. Biol Psychiatry. 2007;61:957–965. 269. Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wüst S. Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav. 2009;55(2):292–298. 270. Beddoe AE, Lee KA. Mind-body interventions during pregnancy. J Obstet Gynecol Neonatal Nurs. 2008;37(2):165–175. https://doi.org/10.1111/ j.1552-6909.2008.00218.x. 271. Clapp M, Aurora N, Herrera L, Bhatia M, Wilen E, Wakefield S. Gut microbiota’s effect on mental health: the gut-brain axis. Clin Pract. 2017;7(4):987. https://doi.org/10.4081/cp.2017.987. 272. Engelberg D, McCutcheon A, Wiseman S. A case of ginseng-induced mania. J Clin Psychopharmacol. 2001;21:535–537. 273. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry. 2016;173(6):575–587. 274. Kanchanatawan B, Tangwongchai S, Sughondhabhirom A, et al. Add-on treatment with curcumin has antidepressive effects in Thai patients with major depression: results of a randomized double-blind placebo-­ controlled study. Neurotox Res. 2018;33(3):621–633. https://doi .org/10.1007/s12640-017-9860-4. 275. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477–479. 276. Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10(1):9–13.

References 277. Taylor MJ, Carney S, Geddes J, Goodwin G. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;4. 278. Levine J, Mishori A, Susnosky M, Martin M, Belmaker RH. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry. 1999;45(3):270–273. 279. Dalton J, Rotondi D, Levitan RD, et al. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25(1):48–52. 280. Berlanga C, Ortega-Soto H, Ontiveros M, Senties H. Efficacy of S adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992;44:257–262. 281. Modabbernia A, Sohrabi H, Nasehi AA, et al. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). 2012;223(4):381–388.

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282. Kashani L, Raisi F, Saroukhani S, et al. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol. 2013;28(1):54–60. https://doi.org/10.1002/hup.2282. 283. Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci. 2000;25(4):337–346. 284. Nowak G, Siwek M, Dudek D, et al. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol. 2003;55(6):1143–1147. 285. Ranjbar E, Kasaei MS, Mohammad-Shirazi M, et al. Effects of zinc supplementation in patients with major depression: a randomized clinical trial. Iran J Psychiatry. 2013;8(2):73–79.

143 Alcohol Dependence Michael T. Murray, ND, and John Nowicki, ND

OUTLINE Diagnostic Summary, 1082 General Considerations, 1082 Genetic Susceptibility, 1082 Alcohol Toxicity and Glutathione, 1084 Intoxication and Withdrawal, 1084 Metabolic Effects of Alcohol and Alcohol Dependence, 1085 Ethanol Metabolism, 1085 Fatty Liver, 1085

DIAGNOSTIC SUMMARY • P  hysical signs of excess alcohol consumption: alcohol odor on breath, flushed face, tremor, ecchymoses • Alcoholic binges, benders (i.e., 48 or more hours of drinking associated with failure to meet usual obligations), or blackouts • Evidence of alcohol-induced illnesses: cirrhosis, gastritis, pancreatitis, myopathy, polyneuropathy, cerebellar degeneration • Psychological/social signs of excess alcohol consumption: depression, loss of friends, arrest for driving while intoxicated, surreptitious drinking, drinking before breakfast, frequent accidents, unexplained work absences • Alcohol dependence manifested when alcohol is withdrawn: tremulousness, convulsions, hallucinations, delirium 

GENERAL CONSIDERATIONS Alcohol dependence, alcohol-use disorder, or, as it was formerly known, alcoholism is a disabling addictive disorder characterized by alcohol consumption that exceeds acceptable cultural limits or injures health or social relationships. Although alcohol (ethanol) can be directly toxic, with resulting symptoms occurring quickly and transiently, toxicity is dose-dependent, and small amounts may be beneficial. Excess is clearly a serious clinical problem in North America, with a prevalence of lifetime alcohol abuse of 17.8% and a prevalence of 12-month alcohol abuse of 4.7%. In the last edition of the TBNM, estimates were that a prevalence of lifetime and 12-month alcohol dependence in the United States is 12.5% and 3.8%, respectively.1 Alcohol dependence is significantly more prevalent among men, whites, Native Americans, younger and unmarried adults, and people with lower incomes. Alcohol dependence affects more than 18 million Americans, making it one of the most serious health problems facing physicians today.1 The total number of Americans affected, either directly or indirectly, is much greater when one considers disruption of family life, automobile accidents, crime, decreased productivity, and mental and physical diseases. With more than 100,000 deaths annually attributed to alcohol misuse, alcohol-related problems are a cause of considerable

1082

Hypoglycemia, 1085 Therapeutic Considerations, 1085 Nutrition, 1085 Psychosocial Aspects, 1087 Miscellaneous Factors, 1087 Therapeutic Approach, 1088 Recommendations for All Four Stages, 1089 Specific Recommendations for Each Stage, 1089

mortality.2 As indicated in Box 143.1, the health, social, and economic consequences of alcohol dependence are alarming. Physicians should consider alcohol dependence when the information provided by the patient and the doctor’s own analysis seems to indicate a missing factor. Often, alcohol dependence is a “hidden” disease. The natural consequences of the alcoholic’s behavior may be disguised by sympathetic family and friends. This circumstance allows the alcoholic to target other factors as the “real problem,” without identifying his or her drinking behavior. Table 143.1 provides an alcohol-dependence–screening questionnaire. The etiology of alcohol dependence remains obscure. It represents a multifactorial condition involving genetic, physiological, psychological, and social factors, each of which seems to be important. Serious drinking often starts in younger people; approximately 35% of alcoholics develop their first symptoms between 15 and 19 years of age, and more than 80% develop their first symptoms before age 30.3 Alcohol dependence is most common in men, but the incidence has been increasing in women. Although the figures were once more disparate, the female-to-male ratio for alcohol dependence has tapered to 1:2.1,2 Women generally seem to develop disease at a lower level of intake than men do. This difference may be partially because of women’s lower volume of distribution for alcohol and may also be related to increased gut permeability to endotoxins.4

Genetic Susceptibility Research indicates that genetic and epigenetic factors may be particularly important (Fig. 143.1).5 For example, individuals with the inactive ALDH2 allele are poor eliminators of acetaldehyde. The resulting accumulation of acetaldehyde produces unpleasant effects from alcohol (e.g., nausea, vomiting, flushing, increased heart rate), and consequently, these individuals consume little to no alcohol. The finding of a genetic marker for susceptibility to alcohol dependence could result in the diagnosis of the disease in its initial and most reversible stage. Some case–control studies suggest that non–gender-based gene polymorphisms encoding cytokines and other immune modulators may play a role in the predisposition to alcoholism. The gene patterns associated

CHAPTER 143 

Alcohol Dependence

1083

BOX 143.1  Consequences of Alcohol

TABLE 143.1  The Brief Michigan Alcohol

Increased Mortality • 10- to 12-year decrease in life expectancy • Double the usual death rate in men, triple in women • Six times greater suicide rate • Major factor in the four leading causes of death in men between the ages of 25 and 44: Accidents, homicides, suicides, cirrhosis 

1. Do you feel you are a normal drinker? 2. Do friends or relatives think you are a normal drinker? 3. Have you ever attended a meeting of Alcoholics Anonymous (AA)? 4. Have you ever lost friends or girlfriends or boyfriends because of drinking? 5. Have you ever gotten into trouble at work because of drinking? 6. Have you ever neglected your obligations, your family, or your work for 2 or more days in a row because you were drinking? 7. Have you ever had delirium tremens (DTs), severe shaking, heard voices, or seen things that were not there after heavy drinking? 8. Have you ever gone to anyone for help about your drinking? 9. Have you ever been in a hospital because of drinking? 10. Have you ever been arrested for drunk driving or driving after drinking?

Dependence

Economic Toll (Yearly) • Lost production: $14.9 billion • Health care costs: $8.3 billion • Accident and fire losses: $5 billion • Cost of violent crime: $1.5 billion • Total costs (health care, accidents, violence, lost productivity): $136 billion  Health Effects • Metabolic damage to every cell • Intoxication • Abstinence and withdrawal syndromes • Nutritional diseases • Cerebellar degeneration • Cerebral atrophy • Psychiatric disorders • Esophagitis, gastritis, ulcer • Increased cancers of the mouth, pharynx, larynx, and esophagus • Pancreatitis • Fatty degeneration and cirrhosis of the liver • Arrhythmias • Myocardial degeneration • Hypertension • Angina • Hypoglycemia • Decreased protein synthesis • Increased serum and liver triglycerides • Decreased serum testosterone • Myopathy • Neuropathy • Osteoporosis • Rosacea, spider veins • Coagulation disorders  Effects on Fetus • Growth retardation • Mental retardation • Fetal alcohol syndrome • Teratogenicity Modified from Hyman SE, Cassem NH. Alcoholism. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American; 1997:III:1-12, 13.

with risk reveal that antibody-mediated mechanisms may play a role in disease pathogenesis.4 The genetic basis of alcohol dependence has also been supported by the following: • Genealogical studies showing that alcohol dependence is a family condition • Studies of adopted children of alcoholic parents raised by foster parents demonstrating a continued higher risk of alcohol dependence • Twin studies showing differences between identical and nonidentical twins

Dependence Screening Test

Yes (0) Yes (0)

No (2) No (2)

Yes (5)

No (0)

Yes (2)

No (0)

Yes (2)

No (0)

Yes (2)

No (0)

Yes (2)

No (0)

Yes (5)

No (0)

Yes (5)

No (0)

Yes (2)

No (0)

Alcohol dependence is indicated by a score above 5. Modified from Hyman SE, Cassem NH. Alcoholism. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, 1997:III, 1-12, 13 Genetic Factors

Environmental Factors

Gene Expression Screening

Alcohol

Identification of Genes Related to Alcoholism

Identification of Epigenetic Factors Impacting Gene Expression

Predisposition

Alcoholism

Development

Fig. 143.1 A hypothetical model for the interactions of genetic and environmental factors in the predisposition to and development of alcoholism. (From Starkman BG, Sakharkar AJ, Pandey SC. Epigenetics— beyond the genome in alcoholism. Alcohol Res. 2012;34[3]:293-305. PubMed PMID: 23134045.)

• A  ssociation with genetic markers: color vision, nonsecretor ABH, HLA-B13, and low platelet monoamine oxidase (MAO) • Biochemical studies showing the importance of alcohol dehydrogenase polymorphism in racial susceptibility to alcohol dependence.5 Several studies have shown that the incidence of alcohol dependence is four to five times more common in the biological children of alcoholic parents than in biological children of nonalcoholic parents.5 Although it would be ultimately useful, knowledge of family history suggests that clear evidence of a biological marker may not be necessary for the implementation of a relatively innocuous primary prevention program. 

1084

SECTION 6 

Diseases

Alcohol Toxicity and Glutathione The diverse toxic effects of alcohol result not only from the variation in the levels of breakdown products but also from the depletion of glutathione. This depletion results in the upregulation of gamma glutamyl transferase (GGT) to provide more glutathione, likely for Phase II conjugation, as well as to neutralize oxidative stress. Cellular GGT metabolizes extracellular GSH, allowing the precursor cysteine to be reused for de novo synthesis of intracellular GSH. There are some major limitations in the use of GGT as a measure of excessive alcohol consumption: 1. GGT also elevates by exposure to other chemicals, especially persistent organic pollutants (POPs) and several prescription drugs. 2. Genetics and nutrient availability will affect GGT’s sensitivity to alcohol consumption. 3. Some chronic imbibers (upward of 9 drinks per day) have GGT in the “normal” range. Individuals have great variation in their ability to produce glutathione in response to toxic and oxidative challenge. Nonetheless, GGT is most beneficial when baseline levels are determined on an individual basis. In a uniform population, GGT will increase in direct proportion to alcohol consumption. In a nonuniform population, 40 g of ethanol per day will elevate GGT ∼15%, whereas 60 g per day for 5 weeks in young men will almost double GGT from 27 to 52 u/L. However, there is much individual variation. In general, GGT goes back to “normal” after abstinence for 1 month. Early research shows promise in using glutathione transferase (GSTA1) as a measure for advising patients on their alcohol consumption, as GSTA1 has been shown to be a sensitive and reliable marker in ethanolinduced hepatic injury.6 

INTOXICATION AND WITHDRAWAL The signs of alcoholic intoxication are typical of a central nervous system depressant: drowsiness, errors of commission, disinhibition, dysarthria, ataxia, and nystagmus. Fifteen milliliters of pure alcohol (the equivalent of 1 oz of whiskey, 4 oz of wine, or 10 oz of beer) raise the blood level of alcohol by 25 mg/dL in a 70-kg person. Table 143.2 shows the effects of varying blood levels of alcohol. Withdrawal symptoms usually occur 1 to 3 days after the last drink. Animal models, as well as findings obtained in humans, have shed light on the effects that acute and chronic alcohol exposure have on signaling systems involving the neurotransmitters glutamate, gamma-­ aminobutyric acid (GABA), dopamine, and serotonin, as well as on other signaling molecules, including endogenous opioids and corticotrophin-releasing factor (CRF) (Fig. 143.2).7 Adaptation to chronic

TABLE 143.2  Effects of Varying Levels of

Blood Alcohol Blood Level (MG/DL) 14 mmol/L) nearly double the risk of AD.63 The importance of a detailed examination in elderly patients with mental symptoms is highlighted by results from a study that analyzed the plasma homocysteine, serum cobalamin, and blood folate in 296 consecutive patients referred to a geriatric psychiatric ward in Sweden for the diagnosis of mental disease.64 Patients who were deficient in vitamin B12 or folic acid or who had elevated levels of homocysteine were given vitamin B12 (dosage not specified) or folic acid (10 mg per day), or both. When individuals with low cobalamin levels were supplemented with vitamin B12, significant clinical improvements were noted. In other studies, supplementation with vitamin B12 has shown tremendous benefit in reversing impaired mental function due to low levels of vitamin B12.57 In one large study, a complete recovery was observed in 61% of similar cases of mental impairment.65 The fact that 39% did not respond is probably a result of long-term low levels of vitamin B12. Several studies have shown that the best clinical

1096

SECTION 6 

Zn

Zn Zn

Diseases

Zinc deficiency Aging?

Zn Zn

Zn Zn

? Neuron terminal

Increased HPA system activity

? Alzheimer’s disease Fig. 144.3 Histochemically reactive zinc level and its relation to the pathogenesis of Alzheimer’s disease. (From Takeda A. Insight into glutamate excitotoxicity from synaptic zinc homeostasis. Int J Alzheimers Dis, 2011; 491597.)

responders are those who have been showing signs of impaired mental function for less than 6 months.34 In one study, 18 subjects with low levels of serum cobalamin and evidence of mental impairment were given vitamin B12. Only those patients who had symptoms for less than 1 year showed improvement.66 The importance of diagnosing and correcting low vitamin B12 levels in the elderly population cannot be overstated. Serum vitamin B12 levels are significantly low and vitamin B12 deficiency is significantly common in AD patients.57,67,68 It has been demonstrated that an oral daily dose as low as 50 mcg can significantly increase serum vitamin B12 levels in vitamin B12–deficient elderly persons.69 Supplementation of vitamin B12, folic acid, or both may result in complete reversal in some patients, but generally there is little improvement in patients who have had AD symptoms for more than 6 months. It has been hypothesized that prolonged low levels of vitamin B12 may lead to irreversible changes that will not respond to supplementation. Vitamin B12 supplementation for elderly subjects with AD will improve hematological parameters but will not usually improve mental function.70 Vitamin B12 is available in several forms. The most common form is cyanocobalamin; however, vitamin B12 is active in the human body in only two forms: methylcobalamin and adenosylcobalamin. Although methylcobalamin and adenosylcobalamin are active immediately on absorption, cyanocobalamin must be converted to either methylcobalamin or adenosylcobalamin by removal of the cyanide molecule and addition of either a methyl or adenosyl group. This conversion may be reduced with aging and may be another factor responsible for the vitamin B12 disturbances noted in the elderly population. 

Zinc Zinc deficiency is one of the most common nutrient deficiencies in elderly people and has been suggested to be a major factor in the development of AD.71 Included in the list of zinc-containing enzymes are most enzymes involved in DNA replication, repair, and transcription. It has been suggested that dementia, possibly because of a long-term zinc deficiency, may represent the long-term cascading effects of error-prone or ineffective DNA-handling enzymes in nerve cells.72 In addition, zinc is required by many antioxidant enzymes, including superoxide dismutase. The end result could be the destruction of nerve cells and the formation of NFTs and plaques. The levels of zinc in the brain and cerebrospinal fluid in patients with AD are markedly decreased, and there is a strong inverse correlation between serum zinc levels and the senile plaque count.73 Dietary zinc deficiency readily decreases serum zinc levels in mice and rats, although it increases serum corticosterone levels through the increased hypothalamic-pituitary-adrenal (HPA) axis activity (Fig. 144.3).74 Zinc deficiency can reduce histochemically reactive zinc

levels, which are estimated to be susceptible to aging. Zinc deficiency, as well as aging, appear to be significant risk factors for AD. Zinc supplementation has demonstrated good benefits in people with AD. In one study, 10 patients with AD were given 27 mg per day of zinc (as zinc aspartate). Only two patients failed to show improvement in memory, understanding, communication, and social contact. In one 79-year-old patient, the response was labeled “unbelievable” by both medical staff and family.75 Unfortunately there does not seem to be much interest in the scientific community in following up these impressive results with zinc therapy. The medical literature acknowledges zinc’s apparent duality as “The Zinc Paradox.”76 Fueling this ambivalence is conflicting information that zinc may be problematic for AD patients because, in vitro, it accelerates the formation of insoluble β-amyloid peptide.77 Although zinc is neurotoxic at high concentrations and accumulates at sites of degeneration, total tissue zinc is markedly reduced in the brains of AD patients. Other research has shown a much higher concentration of copper-zinc superoxide dismutase in and around the damaged brain tissue of AD patients.78 This finding suggests that the increased concentration of zinc in the damaged areas is due to the body’s efforts to neutralize free radicals through the increased local production of dismutases. A possible corollary is that the higher focal levels of zinc result in increased amyloid formation when the free radical scavenging mechanisms have been inadequate. 

Phosphatidylcholine Because dietary phosphatidylcholine can increase acetylcholine levels in the brain in normal patients and AD is characterized by a decrease in cholinergic transmission, it seems reasonable to assume that phosphatidylcholine supplementation would benefit AD patients. However, the basic defect in cholinergic transmission in AD relates to impaired activity of the enzyme acetylcholine transferase. This enzyme combines choline (as provided by phosphatidylcholine) with an acetyl molecule to form acetylcholine, the neurotransmitter. Providing more choline does not necessarily increase the activity of this key enzyme, so phosphatidylcholine supplementation is not beneficial in the majority of patients with AD. Not surprisingly, clinical trials using phosphatidylcholine have largely been disappointing. Studies have shown inconsistent improvements in memory from choline supplementation in both normal and AD patients.79–82 The studies have been criticized for small sample size, low dose of phosphatidylcholine, and poor design. Furthermore, some researchers are questioning the form of choline used.83 Other forms, such as phosphatidylserine or choline alphoscerate,84 may prove more useful in supporting cholinergic transmission. In a patient with mild to moderate dementia, the use of a high-quality phosphatidylcholine preparation may be worth a try. A dosage of 15 to 25 g per day of phosphatidylcholine is required. If there is no noticeable improvement within 2 weeks, supplementation should be discontinued. 

Phosphatidylserine Phosphatidylserine is the major phospholipid in the brain, where it plays a major role in determining the integrity and fluidity of cell membranes. Normally, the brain can manufacture sufficient levels of phosphatidylserine, but a deficiency of methyl donors like S-adenosylmethionine (SAMe), folic acid, and vitamin B12 or essential fatty acids may inhibit the production of sufficient phosphatidylserine. Low levels of phosphatidylserine in the brain are associated with impaired mental function and depression in the elderly. The primary use of phosphatidylserine is in the treatment of depression, impaired mental function, or both in the elderly, and also

CHAPTER 144  in the treatment of AD. To date, the 11 double-blind published studies have all reported the successful use of phosphatidylserine in the treatment of age-related cognitive decline, AD, or depression.85–95 In the largest study, a total of 494 elderly patients (between 65 and 93 years of age) with moderate to severe senility were given either phosphatidylserine (100 mg three times a day) or a placebo for 6 months.95 The patients were assessed for mental performance, behavior, and mood at the beginning and end of the study. Statistically significant (P 2% Hypoproliferative

< 2% Hypoproliferative Iron deficiency anemia

Macrocytic anemia MCV > 100

Normal iron Normal/high TIBC, normal Tsat

Hemoglobin electrophoresis in patients with high-risk ethnicity +/– DNA testing

Leukemias Aplastic anemia Pure red cell aplasia (expect changes in other cell lines) Hypothyroidism Anemia of chronic disease

Acute blood loss Hemolytic anemia (DAT, LDH, haptoglobin, indirect bilirubin, blood smear [spherocytes or schistocytes])

Megaloblastic (Oval megalocytes/ hypersegmented neutrophils)

Nonmegaloblastic

Vitamin B12 and/or folate deficiency Consider: Drug-induced

Alcohol abuse Myelodysplastic syndrome Liver disease Hypothyroidism Reticulocytosis Consider: drug induced

Thalassemia DAT = direct antiglobulin test (direct Coombs' test): LFT = liver function tests; LDH = lactate dehydrogenase; MCV = mean corpuscular volume; TIBC = total iron-binding capacity; TSH = thyroid-stimulating hormone. Tsat=transferrin saturation *Not covered in all provinces. Sources: 1) BMJ Best Practice. Assessment of anaemia. London: BMJ; 2016. 2) Anemia Review Panel. Anemia Guidelines for Family Practice. 3rd ed. Toronto: MUMS Guideline Clearinghouse: 2014. © The Foundation for Medical Practice Education, www.fmpe.org August 2017

Fig. 145.5 Algorithm for the assessment of anemia. (Waters, H. Anemia in Adults, Practice-based Small Group Learning Program; Hamilton. 2017; 25(10):1-19.)

THERAPEUTIC CONSIDERATIONS Treatment of anemia is dependent on proper clinical evaluation to determine the origin of the anemia. It is critical that the underlying cause of the anemia be uncovered if the correct therapy is to be employed. 

GENERAL NUTRITIONAL SUPPORT FOR ALL TYPES Increasing iron levels in food may help partially or completely overcome poor iron absorption. Animal proteins are a rich source of heme iron, and dark green leafy vegetables are among the best sources of nonheme iron. Although many individuals shy away from organ meats, liver is an excellent source of iron as well as B vitamins. Lamb and venison also contain significant levels of iron and are leaner and less inflammatory than beef. In addition to iron, green leafy vegetables contain natural fat-soluble chlorophyll and nutrients such as vitamin C and folic acid. The chlorophyll molecule is similar to the hemoglobin molecule. Fat-soluble (but not water-soluble) chlorophyll products may be beneficial. However, water-soluble chlorophyll is not absorbed from the gastrointestinal tract and therefore has no use in the treatment of anemia. Because a large percentage of individuals with anemia do not secrete enough hydrochloric acid, it is often important for them to take hydrochloric acid supplements with meals. See Chapter 123, Digestive Support.

Iron-Deficiency Anemia In iron-deficiency anemia, it is essential to determine the reason for the loss of iron (e.g., chronic blood loss) or the reason for the poor

absorption of dietary iron (e.g., low vitamin C or high tannins in diet). Lack of hydrochloric acid is a common reason for impaired iron absorption, especially among elderly persons. There are two forms of dietary iron: heme iron and nonheme iron. Heme iron is bound to the oxygen-binding proteins hemoglobin and myoglobin. Heme iron is the most efficiently absorbed form of iron. The absorption rate of nonheme iron supplements, such as ferrous sulfate and ferrous fumarate, is 2.9% on an empty stomach and 0.9% with food. This rate is significantly less than the absorption rate of heme iron, which is as high as 35%. In addition, heme iron does not cause the side effects associated with nonheme sources of iron, such as nausea, flatulence, constipation, and diarrhea. Despite the superiority of heme iron, nonheme iron salts are the most popular iron supplements. Although heme iron is better absorbed, dosing higher quantities of nonheme iron salts results in similar net absorption amounts (i.e., 3 mg of heme iron and 50 mg of nonheme iron will net approximately the same level of absorption). In adults with iron deficiency anemia, treatment involves the use of 50 to 150 mg elemental iron daily in divided doses. The usual recommendation for any nonheme source is generally up to 60 mg daily in divided doses. For children with iron-deficiency anemia, the dose is 4 to 6 mg/kg per day divided into three doses. High intakes of other minerals, particularly calcium, magnesium, and zinc, can interfere with iron absorption. Therefore, when treating iron deficiency, it is recommended to take iron away from these minerals. In contrast, vitamin C enhances iron absorption. Ferrous sulfate is the most popular iron supplement, but it is certainly less than ideal, because it often causes constipation or other

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TABLE 145.1  Dietary Sources of Iron

TABLE 145.2  Recommended Dietary

Allowances (RDA) for Iron

Food

Average Serving Size (g)

Iron (mg) Per Serving

Group

Daily Dose

Calf or lamb liver

60

9.6

Infants 7–12 months

11 mg

Beef or chicken liver

60

5.2

Children 1–3 years

7 mg

Beef

90

2.7

Children 4–8 years

10 mg

Beans cooked

100

2.3

Males 9–13 years

8 mg

Prunes

100

1.8

Males 14–18 years

11 mg

Bread (3 slices)

70

1.7

8 mg

Chicken or turkey

90

1.6

Males ≥ 19 years Females 9–13 years

8 mg

Greens, cooked

75

1.5

Females 14–18 years

15 mg

Peas

75

1.5

Females 19–50 years

18 mg

Eggs

50

1.1

Females ≥ 51 years

8 mg

Pregnant women

27 mg

Females when lactating between 14–18 years

10 mg

Females when lactating ≥19 years

9 mg

gastrointestinal disturbance. The best forms of nonheme iron are ferrous succinate, glycinate, fumarate, and pyrophosphate. Of these, the preferred form is micronized ferrous pyrophosphate, which is then microencapsulated to allow it to be dispersed and assimilated. Advantages of this form include stability, lack of taste or flavor, and lack of gastrointestinal side effects. In addition, ferrous pyrophosphate provides a sustained-release form of iron (up to 12 hours) with a high relative bioavailability, especially when taken on an empty stomach.12 The best dietary source of iron is red meat, as well as liver and fish. Nonmeat sources of iron include beans, molasses, dried fruits, wholegrain and enriched breads, and green leafy vegetables. Nonheme iron absorption is enhanced by vitamin C. Table 145.1 provides the iron content per serving of some food sources of iron. The table does not factor in absorption. For example, the absorption rate for calf’s liver is nearly 30%, whereas the absorption rate for the vegetable sources is approximately 5%. The daily dietary recommended allowance for iron depends on an individual’s age and gender (Table 145.2). Several foods and beverages contain substances that inhibit iron absorption, including tea, coffee, wheat bran, and egg yolk. Antacids and overuse of calcium supplements also decrease iron absorption. These items should be restricted in the diet of individuals who have iron deficiency. Iron supplements can decrease the availability of several medications, including levodopa and levothyroxine, and care should be exercised when simultaneous administration of these substances is indicated.

Cautions and Warnings Keep all iron supplements out of the reach of children. Acute iron poisoning in infants can result in serious consequences. Severe iron poisoning is characterized by damage to the intestinal lining, liver failure, nausea and vomiting, and shock. 

Pernicious Anemia The usual dietary sources of vitamin B12 are animal-derived foods. The richest sources are liver and kidney, followed by eggs, fish, cheese, and meat. Strict vegetarians and vegans have an increased risk of B12 deficiency, and therefore it is necessary to identify plant-derived foods that contain high levels of vitamin B12—produced by the bacteria, typically in some kind of fermented form. A survey of naturally occurring and high vitamin B12-containing plant-derived food sources showed that nori is a good vitamin B12 source for vegetarians.13 Consumption of

approximately 4 g of dried nori (vitamin B12 content: 77.6 μg/100 g dry weight) supplies the RDA of 2.4 μg per day. Vitamin B12 is available in several forms. The most common form is cyanocobalamin. However, vitamin B12 is active in only two forms: methylcobalamin and adenosylcobalamin. Both forms are available commercially in tablet form in the United States. Although methylcobalamin is active immediately upon absorption, cyanocobalamin must be converted by the body to either methylcobalamin or adenosylcobalamin by removing the cyanide molecule and adding either a methyl or adenosyl group. Cyanocobalamin is not active in many experimental models, whereas both methylcobalamin and adenosylcobalamin demonstrate high-level activity. Medical treatment involves injecting vitamin B12 at a dose of 1 mg daily for 1 week, until the anemia has resolved. Preventive injections may also be required to prevent deficiency in the future. Oral therapy has been shown to be equally effective.

Oral Versus Injectable B12 Although it is popular to inject vitamin B12, injection is not strictly necessary. Studies show that supplementation with oral vitamin B12 is a safe and effective treatment for the B12 deficiency state, even in the absence of intrinsic factor. In the United States, oral vitamin B12 therapy is rarely used even though it has been shown to be 100% effective in the long-term treatment of pernicious anemia.14 Soon after vitamin B12 was isolated in 1948, it was introduced in an injectable form, and researchers busily sought an oral alternative. Oral preparations containing intrinsic factor were tried, but some patients developed antibodies against intrinsic factor and therefore would not respond. Studies in the 1950s and 1960s documented that a small but constant proportion of an oral dose of cyanocobalamin at a dosage of 300 mcg to 1000 mcg daily was absorbed even without intrinsic factor through the process of diffusion. Thus by sufficiently increasing the dose, adequate absorption could be attained. A study in 1978 described 64 Swedish patients with pernicious anemia and other vitamin B12deficiency states who were treated with 1000 mcg of oral cyanocobalamin daily.15 Complete normalization of serum levels and liver stores for vitamin B12, as well as full clinical remission, was observed in all patients studied over a 3-year period. Since then, several studies have validated the use of oral vitamin B12 in the treatment of pernicious anemia.16

CHAPTER 145  Despite the research, the use of oral vitamin B12 therapy remains uncommon in the United States. In a survey of internists, 91% erroneously believed that vitamin B12 could not be absorbed in sufficient quantities without intrinsic factor.17 Interestingly, 88% of these surveyed doctors also stated that an effective oral vitamin B12 therapy would be useful in their practice and further stated that it would be their preferred method of delivery if it were effective. Studies established that the average absorption rate of oral cyanocobalamin by patients with pernicious anemia is 1.2% across a wide range of dosages. Because the daily turnover rate is about 2 mcg, an oral dosage of 200 to 250 mcg daily results in an average absorption of 2.4 to 3 mcg, respectively, which may be adequate for most patients. However, higher doses are often prescribed to ensure effective treatment. In the treatment of pernicious anemia, the usual intramuscular (IM) dosage recommended by most medical texts is 1000 mcg IM weekly for 8 weeks, then once a month for life. For oral vitamin B12, the recommended dosage is 2000 mcg daily (14,000 mcg weekly) for at least 1 month, followed by a daily intake of 1000 mcg of vitamin B12. Methylcobalamin, the active form of B12, is preferred over cyanocobalamin. 

Folic Acid–Deficiency Anemia Dietary foods high in folic acid include liver, asparagus, dried beans, brewer’s yeast, dark green leafy vegetables, and whole grains. Because folic acid is destroyed by heat and light, fruits and vegetables should be eaten fresh or with very little cooking. To replenish folic acid stores, 800 to 1000 mcg of active folate should be taken every day for up to 1 month. Folic acid is available as folic acid (folate) and folinic acid (5-methyl-tetra-hydrofolate). To utilize folic acid, the body must first convert it to tetrahydrofolate and then add a methyl group to form methyl-tetrahydrofolate (folinic acid). Methyl-tetrahydrofolate is the most active form of folic acid and has been shown to be more efficient at raising body stores than folic acid.18 Supplying the body with methyl-tetrahydrofolate bypasses these steps and is needed for those with a genetic inability to make the conversion. 

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1107

THERAPEUTIC APPROACH General Recommendations Effective therapy for anemia is dependent on proper classification as to its cause. Blood tests should be performed every 1 to 2 months to determine the efficacy of treatment. 

Diet Perhaps the best food for individuals with anemia is calf’s liver. Ingestion of 4 to 6 oz of calf’s liver 3 times per week is an option. In addition, the liberal consumption of green leafy vegetables is recommended. 

NUTRITIONAL SUPPLEMENTS Iron-Deficiency Anemia • I ron: 30 mg, bound to either pyrophosphate, succinate, glycinate, or fumarate, twice per day between meals (if this recommendation results in abdominal discomfort, patients should take 30 mg with meals twice per day) • Vitamin C: 1 gram 3 times per day with meals 

B12-Deficiency Anemia • O  ral vitamin B12 (methylcobalamin): 2000 mcg per day sublingually for at least 1 month; adjust dosage according to laboratory results • 5-MTHF: 800 to 1200 mcg 3 times per day 

Folic Acid–Deficiency Anemia • 5 -MTHF: 800 to 1200 mcg 3 times per day • Vitamin B12: 1000 mcg per day; supplementing vitamin B12 with folate prevents the folic acid supplement from masking a vitamin B12 deficiency

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Kuhn V, Diederich L, Keller TCS, et al. Red blood cell function and dysfunction: redox regulation, nitric oxide metabolism, anemia. Antioxid Redox Signal. 2017;26(13):718–742. PubMed PMID: 27889956. 2. Sharp PA. Intestinal iron absorption: regulation by dietary & systemic factors. Int J Vitam Nutr Res. 2010;80(4-5):231–242. 3. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75(5):671–678. 4. Guyatt GH, Oxman AD, Ali M, Willan A, et al. Laboratory diagnosis of iron-deficiency anemia: an overview [published correction appears in J Gen Intern Med. 1992:7, 423]. J Gen Intern Med. 1992;7:145–153. 5. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Family Physician. 2007;75(5):671–678. PubMed PMID: 17375513. 6. Arvidsson B, Ekenved G, Rybo G, Sölvell L. Iron prophylaxis in menorrhagia. Acta Ob Gyn Scand. 1981;60:157–160. 7. Taymor ML, Sturgis SH, Yahia C. The etiological role of chronic iron deficiency in production of menorrhagia. JAMA. 1964;187:323–327. 8. Haas JD, Brownie TIV. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nut. 2001;131(2S–2):676S–690S. PubMed PMID: 11160598. 9. Hannibal L, Lysne V, Bjørke-Monsen AL, et al. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Biosci. 2016;3:27. PubMed PMID: 27446930.

10. Schnog JB, Duits AJ, Muskiet FA, ten Cate H, et al. Sickle cell disease; a general overview. Netherlands J Med. 2004;62(10):364–374. PubMed PMID: 15683091.  11. Elnicki DM, Shockcor WT, Brick JE, Beynon D. Evaluating the complaint of fatigue in primary care: diagnoses and outcomes. Am J Med. 1992;93:303– 306. 12. Fidler MC, Walczyk T, Davidsson L, et al. A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr. 2004;91(1):107–112. 13. Watanabe F, Yabuta Y, Bito T, Teng F. Vitamin B12-containing plant food sources for vegetarians. Nutrients. 2014;6(5):1861–1873. PubMed PMID: 24803097. 14. Andrès E, Dali-Youcef N, Vogel T, Serraj K, et al. Oral cobalamin (vitamin B12) treatment. An update. Int J Lab Hematol. 2009;31(1):1–8. 15. Berlin R, Berlin H, Brante G, Pilbrant A. Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia. Acta Med Scand. 1978;204(1–2):81–84. 16. Oh R, Brown DL. Vitamin B12 deficiency. Am Family Physician. 2003;67(5):979–986. PubMed PMID: 12643357. 17. Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geriatr Society. 1998;46(9):1125–1127. PubMed PMID: 1125-7. 18. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010;49(8):535–548.

1107.e1

146 Angina Michael T. Murray*, ND, and John Nowicki, ND

OUTLINE Diagnostic Summary, 1108 General Considerations, 1108 Diagnostic Considerations, 1108 Therapeutic Considerations, 1108 Nutritional Supplements for Angina, 1110 Botanical Medicines, 1111 Other Therapies, 1112

Intravenous Ethylenediaminetetraacetic Acid (EDTA) Chelation Therapy, 1112 Therapeutic Approach, 1112 Diet, 1112 Lifestyle, 1112 Nutritional Supplements, 1112 Botanical Medicines, 1113

DIAGNOSTIC SUMMARY

DIAGNOSTIC CONSIDERATIONS

• S queezing or pressure-like pain in the chest appearing immediately after exertion. Other precipitating factors include emotional tension, cold weather, or a large meal. Pain may radiate to the left shoulder blade, left arm, or jaw. The pain typically lasts for only 1 to 20 minutes. • Stress, anxiety, and high blood pressure are typically present. • Most people demonstrate an abnormal electrocardiographic reading (transient ST-segment depression) in response to light exercise (stress test). 

The diagnosis of angina is frequently made by history alone. Clinical evaluation of all patients with angina should include an electrocardiogram (ECG) at rest and a chest radiograph. Because more than one half of patients with typical angina and confirmed coronary atherosclerosis have normal 12-lead ECG readings at rest, diagnosis must often be confirmed using ECG stress testing or 24-hour Holter monitoring (ambulatory ECG). The most common diagnostic ECG changes associated with angina are evidence of previous MI and ST-segment and T-wave changes that occur during attacks of pain. The most characteristic change is displacement of the ST segment with or without T-wave inversion (Fig. 146.2). Complicating diagnosis, however, is the observation that hypoglycemia-induced angina does not manifest with rate or ST-segment abnormalities.1 

GENERAL CONSIDERATIONS Angina pectoris results when the supply of oxygen, and occasionally other nutrients, is inadequate to meet the metabolic needs of the heart muscle. The primary cause is atherosclerosis, although platelet aggregation, coronary artery spasm, nonvascular mechanisms such as hypoglycemia, and incre­ased metabolic need (such as in hyperthyroidism) can also be important. The primary lesion of atherosclerosis is the atheromatous plaque, which progressively narrows and ultimately blocks the coronary artery, resulting in a decreased supply of blood and oxygen to the heart tissue. Symptoms typically begin to appear after a major coronary artery is blocked by more than 50%. Blood flow to the heart may also be compromised by transient platelet aggregation (discussed in more detail in Chapter 149) and coronary artery spasm. Prinzmetal’s variant angina, the most commonly recognized form of coronary artery spasm, is not due to plaque in the coronary arteries and is more apt to occur at rest or at odd times during the day or night. It is more common in women younger than age 50. Magnesium insufficiency–induced coronary artery spasm, more common in men than women, is now recognized as an important cause of myocardial infarction (MI) and may be of significance in angina pectoris (Fig. 146.1). 

*Previous edition contributor

1108

THERAPEUTIC CONSIDERATIONS Angina is a serious condition that requires careful treatment and monitoring. In the severe case as well as in the initial stages of mild to moderate angina, prescription medications may be necessary. Eventually the condition should be controlled with the help of natural measures. If there is significant blockage of the coronary artery, intravenous ethylenediaminetetraacetic acid (EDTA) chelation therapy, angioplasty, or coronary artery bypass may be appropriate. From the perspective of natural medicine, there are two primary therapeutic goals in the treatment of angina: improving energy metabolism within the heart and improving blood supply to the heart. These goals are interrelated, as an increased blood flow means improved energy metabolism, and vice versa. The heart uses fats as its major metabolic fuel. It converts free fatty acids to energy in much the same way as an automobile uses gasoline. Defects in the utilization of fats by the heart greatly increase the risk of atherosclerosis, heart attacks, and anginal pains. Specifically, impaired utilization of fatty acids by the heart results in the accumulation of high concentrations of fatty acids within the heart muscle.

CHAPTER 146 

Age

Smoking

C-reactive protein

Ergot alkaloid (ergonovine)

Activated platelets Cold pressor (sympathetic activation)

Physical/mental stress

Angina

Sympathomimetics (epinephrine, norepinephrine)

Coronary artery spasm

Parasympathomimetics (acetylcholine, pilocarpine) Non-selective βblockers (propranolol)

Valsalva maneuver

Central nervous system stimulants (cocaine)

Remnant lipoproteins Hyperventilation (alkalosis)

Magnesium deficiency (alcohol)

Fig. 146.1  Risk factors and precipitating factors for coronary artery spasm. (From Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. Int J Med Sci. 2014;11[11],1161-71.)

Risk Factors: • Hypotension • Exercise • Emotional stress • Anemia • Cold weather Silent ischemia Atherosclerosis

Without

Chronic stable Angina

With thrombosis

With embolism Unstable Angina Without embolism Acute Coronary Syndrome

STEMI NSTEMI

STEMI = ST-Segment Elevation Myocardial Infarction NSTEMI = Non-ST Segment Myocardial Infarction Fig. 146.2 Algorithm of diagnostic in coronary artery disease. (Retrieved from Non-Invasive Imaging in Approaching Ischemic Coronary Artery Disease—Scientific Figure on ResearchGate. Available from: https:// www.researchgate.net/figure/Algorithm-of-diagnostic-in-coronary-artery-disease-High-risk-of-coronaryartery-disease_fig1_221916523 [accessed May 14, 2019])

1109

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This accumulation makes the heart extremely susceptible to cellular damage, which ultimately leads to a heart attack. Carnitine, pantethine, and coenzyme Q10 (CoQ10) are essential compounds in normal fat and energy metabolism and are of extreme benefit to sufferers of angina. These nutrients prevent the accumulation of fatty acids within the heart muscle by improving the conversion of fatty acids and other compounds into energy.

Nutritional Supplements for Angina

metabolites. These compounds are extremely deleterious because they activate various phospholipases and disrupt cellular membrane structures. The changes in the properties of cardiac cell membranes induced by fatty-acid metabolites are thought to contribute to impaired heart muscle contractility and compliance, increased susceptibility to irregular beats, and the eventual death of heart tissue. Supplemental carnitine increases heart carnitine levels and prevents the production of toxic fatty-acid metabolites. This mechanism has been demonstrated clinically, where the early administration of l-carnitine (40 mg/kg per day) in patients having heart attacks was found to considerably reduce heart damage.11 

The use of antioxidant supplementation in patients with angina is important. In an analysis of normal controls and patients with either stable or unstable angina, the plasma level of antioxidants has been shown to be a more sensitive predictor of unstable angina than the severity of atherosclerosis.2,3 One group of researchers concluded: “These data are consistent with the hypothesis that the beneficial effects of antioxidants in coronary artery disease (CAD) may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed disease.”2 Antioxidant nutrients are also important in preventing nitrate tolerance. Oral nitrates are widely used in the conventional treatment of angina, but their continuous administration can result in the rapid development of tolerance. Experimental findings indicate that nitrate tolerance is associated with increased vascular production of superoxide. The superoxide anions generated quickly degrade the nitric oxide formed from the administration of nitroglycerin and result in lower levels of cyclic guanosine monophosphate (an important intracellular regulator that promotes vasorelaxation). Because vitamin C is the main aqueous-phase antioxidant and free radical scavenger of superoxide and vitamin E is the main lipid-phase antioxidant, their importance in preventing nitrate tolerance is obvious. Clinical trials have upheld this connection, showing that high-dose supplementation of vitamins C and E can prevent nitrate tolerance.4,5

Pantethine is the stable form of pantetheine, the active form of pantothenic acid, which is the fundamental component of coenzyme A (CoA). CoA is involved in the transport of fatty acids to and from cells as well as to the mitochondria. The synthetic pathway from pantethine to CoA is much shorter than that of pantothenic acid, making pantetheine the preferred therapeutic substance. In addition, pantetheine has significant lipid-lowering activity, whereas pantothenic acid has very little if any effect in lowering cholesterol and triglyceride levels. The standard dose for pantethine is 900 mg per day. Like carnitine, pantethine has been shown in clinical trials to significantly reduce serum triglyceride and cholesterol levels and to increase high-density-lipoprotein cholesterol levels.12-14 Its lipid-lowering effects are most impressive when its toxicity (virtually none) is compared with that of conventional lipid-lowering drugs. Its mechanism of action is due to the inhibition of cholesterol synthesis and acceleration of fatty acid breakdown in the mitochondria. Pantethine is well indicated in angina. Like carnitine, heart pantethine levels decrease during times of reduced oxygen supply. Demonstrated effects in animals indicate that it would greatly benefit individuals with angina.15 

Carnitine

Coenzyme Q10

Carnitine, a vitamin-like compound, stimulates the breakdown of long-chain fatty acids by the energy-producing units in cells—the mitochondria. Carnitine is essential in the transport of fatty acids into the mitochondria. A deficiency in carnitine results in a decrease in fatty-acid concentrations in the mitochondria and reduced energy production. Normal heart function is critically dependent on adequate concentrations of carnitine. Although the normal heart stores more carnitine than it needs, if the heart does not have a good supply of oxygen, carnitine levels quickly decrease. This decrease leads to decreased energy production in the heart and increased risk for angina and heart disease. Because angina patients have a decreased supply of oxygen, carnitine supplementation makes good sense. Several clinical trials have demonstrated that carnitine improves angina and heart disease.6-10 Supplementation with carnitine normalizes heart carnitine levels and allows the heart muscle to use its limited oxygen supply more efficiently. This increased efficiency translates to an improvement in cases of angina. Improvements have been noted in exercise tolerance and heart function and suggest that carnitine is an effective alternative to drugs in cases of angina. In one study of patients with stable angina, oral administration of 900 mg of l-carnitine increased mean exercise time and the time necessary for abnormalities to occur on a stress test (6.4 minutes in the placebo group compared with 8.8 minutes in the carnitine-treated group).10 These results indicate that carnitine may be an effective alternative to other antianginal agents such as beta blockers, calcium channel antagonists, and nitrates, especially in patients with chronic stable angina pectoris. Carnitine, by improving fatty-acid utilization and energy production in the heart muscle, may also prevent the production of toxic fatty-acid

CoQ10, also known as ubiquinone, is an essential component of the mitochondria, where it plays a major role in energy production. Like carnitine and pantethine, CoQ10 can be synthesized in the body. Nonetheless, deficiency states have been reported. Deficiency can be a result of impaired CoQ10 synthesis due to nutritional deficiencies, a genetic or acquired defect in CoQ10 synthesis, or increased tissue needs.16 Cardiovascular diseases—including angina, hypertension, mitral valve prolapse, and congestive heart failure—are examples of diseases that require increased tissue levels of CoQ10.16 In addition, many elderly persons may have increased CoQ10 requirements; the decline of CoQ10 levels that occurs with age may be partly responsible for the age-related deterioration of the immune system. CoQ10 deficiency is common in individuals with heart disease. Heart tissue biopsies in patients with various heart diseases show a CoQ10 deficiency in 50% to 75% of cases.16 One of the most metabolically active tissues in the body, the heart may be unusually susceptible to the effects of CoQ10 deficiency. Accordingly, CoQ10 has shown great promise in the treatment of heart disease. In one study, 12 patients with stable angina pectoris were treated with CoQ10 (150 mg per day for 4 weeks) in a double-blind crossover trial.17 In comparison with placebo, CoQ10 reduced the frequency of anginal attacks by 53%. In addition, researchers found a significant increase in treadmill exercise–tolerance (time to onset of chest pain and time to development of ECG abnormalities) during CoQ10 treatment. The results of this study and others suggest that CoQ10 is a safe and effective treatment for angina pectoris. Carnitine, pantethine, and CoQ10 should be considered in all heart disorders, not just angina. 

Pantethine

CHAPTER 146 

Magnesium Magnesium deficiency may play a major role in angina, including Prinzmetal’s variant. A magnesium deficiency has been shown to produce spasms of the coronary arteries and is thought to be a cause of nonocclusive heart attacks.18 Furthermore, researchers have observed that men who die suddenly of heart attacks have significantly lower levels of heart magnesium, as well as potassium, compared to matched controls.19 Making magnesium the treatment of choice for angina due to coronary artery spasm has been suggested.19-21 Magnesium administration has also been found to be helpful in the management of arrhythmias and in angina due to atherosclerosis. Its benefit in these situations is presumably via the same mechanisms responsible for its effects in an acute MI. Since the mid-1980s, eight well-designed studies involving more than 4000 patients have demonstrated that intravenous magnesium supplementation during the first hour of admission to a hospital for an acute MI produces a favorable effect in reducing immediate and longterm complications as well as death rates.22-24 The beneficial effects of magnesium in acute MI relate to its ability to: • Improve energy production within the heart • Dilate the coronary arteries, resulting in improved delivery of oxygen to the heart • Reduce peripheral vascular resistance, resulting in reduced demand on the heart • Inhibit platelets from aggregating and forming blood clots • Reduce the size of the infarct (blockage) • Improve heart rate and arrhythmias 

Arginine Arginine supplementation has been shown to be beneficial in several cardiovascular diseases, including angina pectoris. Its benefit is thought to occur via increasing nitric oxide levels, thereby improving blood flow, reducing thrombosis, and improving rheology. The degree of improvement offered by arginine supplementation in angina and other cardiovascular diseases can be quite significant as a result of improved nitric oxide levels. In double-blind studies, it has been shown to be especially effective in increasing exercise tolerance. Typical dosage is 6 g per day in divided dosages.25-27 In a short-term study, arginine supplementation of 3 g per day for 15 days resulted in increased activity of the free-radical scavenging enzyme superoxide dismutase and increased the levels of total thiols and ascorbic acid, with a concomitant decrease in lipid peroxidation, carbonyl content, serum cholesterol, and the activity of the prooxidant enzyme xanthine oxidase.28 These beneficial changes point to additional mechanisms for the use of arginine in angina and cardiac ischemia. Use of arginine is cautioned by a report in one study in survivors of MI in whom supplementation with arginine (9 g per day for 6 months) was associated with an increase in mortality compared with the placebo group (8.6% vs. 0%).29 This effect may have been an aberration or due to the use of higher dosages of arginine. 

Botanical Medicines Crataegus Species

Hawthorn berry and extracts of the flowering tops are widely used in Europe for their cardiovascular activity. They exhibit a combination of effects that are of great value to patients with angina and other heart problems. Numerous experiments and clinical studies have documented the cardiovascular efficacy of the plant through various mechanisms, including positive inotropic and negative chronotropic effects; escalation in coronary blood flow and exercise tolerance; inhibition of

Angina

1111

the enzymes, such as angiotensinconverting enzyme (ACE) and phosphodiesterase; providing anti-inflammatory and antihyperlipidemic effects; and improving status of antioxidant enzymes, which support its cardioactive efficacy.30 Studies have demonstrated that hawthorn extracts are effective in reducing anginal attacks as well as in lowering blood pressure and serum cholesterol levels.31-33 The beneficial effects in the treatment of angina are due to improvement in the blood and oxygen supply of the heart resulting from dilation of the coronary vessels, as well as improvement of the metabolic processes in the heart.31-35 The ability of Crataegus species to dilate coronary blood vessels has been repeatedly demonstrated in experimental studies.31-33 In addition, Crataegus extracts have been shown to improve cardiac energy metabolism in human and experimental studies. This combined effect is extremely important in the treatment of angina because it results in improved myocardial function with more efficient use of oxygen. This improvement results not only from increased blood and oxygen supply to the heart muscle but also from hawthorn flavonoids interacting with key enzymes to enhance myocardial contractility. Because adhesion molecules play an important role in the development and progression of coronary atherosclerosis, one study evaluated the effect of Cratagol herbal tablets, aerobic exercise, and their combination on the serum levels of Intercellular Adhesion Molecule (ICAM)-1 and E-Selectin in patients with stable angina pectoris.34 Eighty stable angina pectoris patients age 45 to 65 years were randomly divided into four groups including three experimental groups and one control group: aerobic exercise (E), C. oxyacantha extract (S), aerobic exercise and C. oxyacantha extract (S+E), and control (C). After 12 weeks of treatment, intergroup comparison of the data revealed a significant reduction (P < 0.01) in serum levels of ICAM-1 and E-selectin in experimental groups. The authors concluded that aerobic exercise and consuming C. oxyacantha extract present an effective complementary strategy to significantly lower the risk of atherosclerosis and heart problems. (See Chapter 71 for a comprehensive discussion of this important botanical.) 

Ammi visnaga Khella is a medicinal plant native to the Mediterranean region, where it has been used in the treatment of angina and other heart ailments since the time of the pharaohs. Several of its components have demonstrated the ability to dilate the coronary arteries. Its mechanism of action appears to be similar to that of the calcium channel blocking drugs. Since the late 1940s, there have been numerous scientific studies on the clinical effect of khella extracts in the treatment of angina. More specifically, khellin, a derivative of the plant, was shown to be extremely effective in relieving anginal symptoms, improving exercise tolerance, and normalizing ECGs. This finding is evident by the concluding statements in a study by Osher and colleagues35 in 1951: “The high proportion of favorable results, together with the striking degree of improvement frequently observed, has led us to the conclusion that khellin, properly used, is a safe and effective drug for the treatment of angina pectoris.” At higher doses (120–150 mg per day), pure khellin was associated with mild side effects, such as anorexia, nausea, and dizziness. Although most clinical studies used high dosages, several studies show that as little as 30 mg per day appears to offer as good results with fewer side effects.36,37 Rather than using the isolated compound khellin, khella extracts standardized for khellin content (typically 12%) are the preferred form. A daily dose of such an extract would be 250 to 300 mg. Khella appears to work well with hawthorn extracts. 

1112

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Diseases

Other Therapies Acupuncture

Several studies have shown acupuncture to be of benefit in improving angina, specifically in reducing nitroglycerin use, decreasing the number of anginal attacks, and improving exercise tolerance and ECG readings.38-41 

Relaxation and Breathing Exercises Relaxation and breathing exercises may be helpful in improving anginal symptoms, especially when anxiety is a significant contributor.42,43 In one study in patients with cardiac syndrome X, a form of angina in people with otherwise normal coronary arteries, transcendental meditation (20 minutes twice daily of silently chanting a mantra with eyes closed) was found to reduce angina-like chest pain and to normalize ECGs.42 

Intravenous Ethylenediaminetetraacetic Acid (EDTA) Chelation Therapy EDTA chelation therapy is an alternative to coronary artery bypass surgery and angioplasty, which may prove to be more effective, safer, and less expensive. EDTA is an amino acid–like molecule that, when slowly infused into the bloodstream, binds with minerals such as calcium, iron, copper, and lead and carries them to the kidneys, where they are excreted. EDTA chelation has been commonly used for lead poisoning, but in the late 1950s and early 1960s it was found to help patients with atherosclerosis. The discovery of EDTA chelation therapy in the treatment of angina and other conditions associated with atherosclerosis happened accidentally. In 1956 a battery worker whom Norman Clarke was treating with EDTA for lead poisoning noticed that his symptoms of angina disappeared. Clarke and others began using EDTA chelation therapy in patients with angina, cerebral vascular insufficiency, and occlusive peripheral vascular disease. In a series of 283 patients treated by Clarke and colleagues from 1956 to 1960, a total of 87% showed improvements in their symptoms. Heart patients improved, and patients with blocked arteries in the legs, particularly those with diabetes, avoided amputation.44,45 It was originally thought that EDTA opened blocked arteries by chelating out the calcium deposits in the cholesterol plaque. However, the benefit now seems more related to chelating out excess iron and copper, minerals that, in the presence of oxygen, stimulate free radicals. Free radicals damage arterial cells, and this damage is a primary cause of atherosclerosis. In a review of the progression and regression of atherosclerosis, the authors write that the process of atherosclerosis is “dependent on the presence of some metals (copper and iron) and can be completely inhibited by chelating agents such as EDTA.”46 Despite obvious benefits to heart patients, EDTA fell out of favor in the mid-1960s. Advocates believe this occurred for two reasons: (1) the lucrative surgical approach to heart and vessel disease was on the rise; and (2) the patent on EDTA that was held by Abbott Laboratories expired, so there was no financial interest for drug companies to fund research. Fortunately, in 1972 a small group of practicing physicians using EDTA chelation therapy founded an organization now called the American College for the Advancement of Medicine to continue education and research in this important area. In the early days of EDTA chelation therapy, several serious problems were discovered. Giving too much EDTA or giving it too fast was soon noted to be dangerous. In fact, several deaths attributed to kidney failure were caused by toxicity to EDTA. Fortunately, additional research resulted in more appropriate protocols, and EDTA chelation

therapy is now safe. No deaths or significant adverse reactions have occurred in more than 500,000 patients who have undergone EDTA chelation therapy. Because EDTA chelation improves blood flow throughout the body, the “side effects” are usually beneficial and only a few adverse effects are noticed. A substantial body of scientific evidence exists on the use of EDTA chelation therapy in the treatment of angina, peripheral vascular disease, and cerebral vascular disease.47-51 Nonetheless, there is a paucity of well-designed placebo-controlled studies to definitively assess the efficacy of this approach. This shortcoming is unfortunate considering the early successes. The conclusion from a Cochrane Review summarizes the situation well: “At present, there is insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of patients with atherosclerotic cardiovascular disease.” For more information, refer to the American College of Advancement in Medicine (ACAM), 23121 Verdugo Drive, Suite 204, Laguna Hills, CA, 92653; 1-800532-3688 (outside California) or 1-800-435-6199 (inside California); www.acam.org. 

THERAPEUTIC APPROACH The primary therapy for angina is prevention, because angina is usually secondary to atherosclerosis. Once angina has developed, restoring proper blood supply to the heart and enhancing energy production within the heart are necessary. Particularly important nutrients for accomplishing these results are vitamins C and E, carnitine, pantethine, CoQ10, magnesium, and arginine. Magnesium is of additional benefit because of its ability to relax spastic coronary arteries and improve heart function. Hawthorn berries or extracts offer several benefits to individuals with angina, including coronary artery dilation and improved heart muscle metabolism. Patients with unstable angina pectoris (characterized by a progressive increase in the frequency and severity of pain, increased sensitivity to precipitating factors, progression of symptoms over several days, and prolonged coronary pain) should be hospitalized.

Diet The dietary guidelines given in Chapter 44 are appropriate here. An increase of dietary fiber is recommended, especially the gel-forming or mucilaginous fibers (e.g., flaxseed, oat bran, pectin). Onions and garlic (both raw and cooked), vegetables, and fish should also be increased, and the consumption of saturated fats, cholesterol, sugar, and animal proteins should be reduced. All fried foods and food allergens should be avoided. Patients with reactive hypoglycemia should eat regular meals and carefully avoid simple carbohydrates in all forms (e.g., sugar, honey, dried fruit, and fruit juice). 

Lifestyle The individual with angina should not smoke or drink alcohol or coffee. Stress should be decreased by using stress management techniques such as progressive relaxation, meditation, or guided imagery. A carefully graded progressive aerobic exercise program (30 minutes three times a week) is a necessity. Walking is a good exercise with which to start. 

Nutritional Supplements • • • •

 itamin C: 500 to 1500 mg a day V Vitamin E: 200 to 400 International Units per day CoQ10: 150 to 300 mg a day l-Carnitine: 500 mg three times a day

CHAPTER 146  • P  antethine: 300 mg three times a day • Magnesium, preferably bound to aspartate, citrate, or other Krebs cycle intermediate: 200 to 400 mg three times a day • Arginine: 1000 to 2000 mg three times a day 

Botanical Medicines •

Crataegus oxyacantha (three times a day) • Berries or flowers (dried): 3 to 5 g or as a tea • Fluid extract (1:1): 2 to 4 mL (0.5–1 tsp) • Solid extract (10% procyanidins or 1.8% vitexin-4′-rhamnoside): 100 to 250 mg

Angina

1113

• Ammi visnaga (three times a day) • Dried powdered extract (12% khellin content): 100 mg three times a day

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Bansal S, Toh SH, LaBresh KA. Chest pain as a presentation of reactive hypoglycemia. Chest. 1983;84:641–662. 2. Kostner K, Hornykewycz S, Yang P, et al. Is oxidative stress causally linked to unstable angina pectoris? A study in 100 CAD patients and matched controls. Cardiovasc Res. 1997;36:330–336. 3. Vita JA, Keaney Jr JF, Raby KE, et al. Low plasma ascorbic acid independently predicts the presence of an unstable coronary syndrome. J Am Coll Cardiol. 1998;31:980–986. 4. Watanabe H, Kakihana M, Ohtsuka S, et al. Randomized, double-blind, placebo-controlled study of ascorbate on the preventive effect of nitrate tolerance in patients with congestive heart failure. Circulation. 1998;97:886– 891. 5. Watanabe H, Kakihana M, Ohtsuka S, et al. Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance. Circulation. 1997;96:2545–2550. 6. Lagioia R, Scritinio D, Mangini SG, et al. Propionyl-L-carnitine: a new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol. 1992;34:167–172. 7. Bartels GL, Remme WJ, Pillay M, et al. Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol. 1994;74:125–130. 8. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res. 1991;17:225–235. 9. Davini P, Bigalli A, Lamanna F. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exptl Clin Res. 1992;18:355–365. 10. Kamikawa T, Suzuki Y, Kobayashi A, et al. Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris. Jpn Heart J. 1984;25:587– 597. 11. Rebuzzi AG, Schiavoni G, Amico CM, et al. Beneficial effects of L-carnitine in the reduction of the necrotic area in acute myocardial infarction. Drugs Exp Clin Res. 1984;10:219–223. 12. Arsenio L, Bodria P, Magnati G, et al. Effectiveness of long-term treatment with pantethine in patients with dyslipidemias. Clin Ther. 1986;8:537–545. 13. Miccoli R, Marchetti P, Sampietro T, et al. Effects of pantethine on lipids and apolipoproteins in hypercholesterolemic diabetic and non-diabetic patients. Curr Ther Res. 1984;36:545–549. 14. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50:73–83. 15. Hayashi H, Kobayashi A, Terad H, et al. Effects of pantethine on action potential of canine papillary muscle during hypoxic perfusion. Jpn Heart J. 1985;26:289–296. 16. Folkers K, Yamamura Y, eds. Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the International Symposium on Coenzyme Q. Vols 1–4. Amsterdam, Netherlands: Elsevier Scientific. 17. Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol. 1985;56:247–251. 18. Turlapaty PD, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science. 1980;208:198–200. 19. Altura BM. Ischemic heart disease and magnesium. Magnesium. 1988;7:57–67. 20. McLean RM. Magnesium and its therapeutic uses: a review. Am J Med. 1994;96:63–76. 21. Purvis JR, Movahed A. Magnesium disorders and cardiovascular disease. Clin Cardiol. 1992;15:556–568. 22. Hampton EM, Whang DD, Whang R. Intravenous magnesium therapy in acute myocardial infarction. Ann Pharmacothe. 1994;28:220–226. 23. Teo KK, Yusuf S. Role of magnesium in reducing mortality in acute myocardial infarction: a review of the evidence. Drugs. 1993;46:347–359. 24. Schecter M, Kaplinsky E, Rabinowitz B. The rationale of magnesium supplementation in acute myocardial infarction: a review of the literature. Arch Intern Med. 1992;152:2189–2196. 25. Bednarz B, Wolk R, Chamiec T, et al. Effects of oral L-arginine supplementation on exercise-induced QT dispersion and exercise tolerance in stable angina pectoris. Int J Cardiol. 2000;75(2-3):205–210.

26. Kobayashi N, Nakamura M, Hiramori K. Effects of infusion of L-arginine on exercise-induced myocardial ischemic ST-segment changes and capacity to exercise of patients with stable angina pectoris. Coron Artery Dis. 1999;10(5):321–326. 27. Ceremuzyński L, Chamiec T, Herbaczyńska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997;80(3):331–333. 28. Tripathi P, Chandra M, Misra MK. Oral administration of L-arginine in patients with angina or following myocardial infarction may be protective by increasing plasma superoxide dismutase and total thiols with reduction in serum cholesterol and xanthine oxidase. Oxid Med Cell Longev. 2009;2(4):231–237. 29. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295(1):58–64. 30. Orhan IE. Phytochemical and Pharmacological Activity Profile of Crataegus oxyacantha L. (Hawthorn) - A Cardiotonic Herb. Curr Med Chem. 2018;25(37):4854–4865. PubMed PMID: 27655074. 31. Ammon HPT, Handel M. Crataegus, toxicology and pharmacology. Part I: Toxicity. Planta Med. 1981;43:105–120. Part II: Pharmacodynamics. Planta Med. 1981;43:209-239; Part III: Pharmacodynamics and pharmacokinetics. Planta Med. 1981;43: 313-322. 32. Blesken R. Crataegus in cardiology. Fortschr Med. 1992;110:290–292. 33. Nasa Y, Hashizume H, Hoque AN, et al. Protective effect of Crataegus extract on the cardiac mechanical dysfunction in isolated perfused working rat heart. Arzneimittelforschung. 1993;43:945–949. 34. Jalaly L, Sharifi G, Faramarzi M. Comparison of the effects of Crataegus oxyacantha extract, aerobic exercise and their combination on the serum levels of ICAM-1 and E-Selectin in patients with stable angina pectoris. Daru. 2015;23:54. PubMed PMID: 26687477. 35. Osher HL, Katz KH, Wagner DJ. Khellin in the treatment of angina pectoris. N Engl J Med. 1951;244:315–321. 36. Anrep GV, Kenawy MR, Barsoum GS. Coronary vasodilator action of khellin. Am Heart J. 1949;37:531–542. 37. Conn JJ, Kissane RW, Koons RA, et al. Treatment of angina pectoris with khellin. Ann Intern Med. 1952;36:1173–1178. 38. Ballegaard S, Karpatschoff B, Holck JA, et al. Acupuncture in angina pectoris: do psychosocial and neurophysiological factors relate to the effect? Acupunct Electrother Res. 1995;20:101–116. 39. Meng J. The effects of acupuncture in treatment of coronary heart diseases. J Tradit Chin Med. 2004;24:16–19. 40. Ballegaard S, Jensen G, Pedersen F, et al. Acupuncture in severe, stable angina pectoris: a randomized trial. Acta Med Scand. 1986;220:307–313. 41. Richter A, Herlitz J, Hjalmarson A. Effect of acupuncture in patients with angina pectoris. Eur Heart J. 1991;12:175–178. 42. Cunningham C, Brown S, Kaski JC. Effects of transcendental meditation on symptoms and electrocardiographic changes in patients with Cardiac Syndrome X. Am J Cardiol. 2000;85:653–655. A10. 43. Gilbert C. Clinical applications of breathing regulation: beyond anxiety management. Behav Modif. 2003;27:692–709. 44. Clarke CN, Clarke NE, Mosher RE. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci. 1956;232:654–666. 45. Sr Clarke NE. Atherosclerosis, occlusive vascular disease and EDTA. Am J Cardiol. 1960;6:233–236. 46. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–924. 47. Cranton EM, Frackelton JP. Current status of EDTA chelation therapy in occlusive arterial disease. J Adv Med. 1989;2:107–119. 48. Olszewer E, Carter JP. EDTA chelation therapy: a retrospective study of 2,870 patients. J Adv Med. 1989;2:197–211. 49. Olszewer E, Sabbag FC, Carter JP. A pilot double-blind study of sodium-magnesium EDTA in peripheral vascular disease. J Nat Med Assoc. 1990;82:173–177. 50. Olszewer E, Carter JP. EDTA chelation therapy in chronic degenerative disease. Med Hypotheses. 1988;27:41–49. 51. Casdorph HR. EDTA chelation therapy, efficacy in arteriosclerotic heart disease. J Holistic Med. 1981;3:53–59.

1113.e1

147 Aphthous Stomatitis Michael Traub, ND, DHANP, FABNO, and Michael T. Murray*, ND

OUTLINE Diagnostic Summary, 1114 General Considerations, 1114 Therapeutic Considerations, 1114 Allergies and Environmental Factors, 1114 Gluten Sensitivity, 1115 Dietary Factors, 1115 Mechanical Injuries, 1115 Hormonal Changes, 1115

DIAGNOSTIC SUMMARY • S ingle or several discrete, shallow, painful ulcers found anywhere on the oral mucosa: labial and buccal mucosa, maxillary and mandibular sulci, gingiva, soft palate, tonsillar fauces, floor of the mouth, ventral surface of the tongue. • 75% to 90% of recurrent aphthous ulcers (RAU) are 5 to 10 mm in size, shallow, and classified as minor aphthae • 10% to 15% of RAU are greater than 10 mm in size, deep, and classified as major aphthae. • Lesions have fairly even borders, are surrounded by an erythematous halo, and eventually are covered by a fibrous pseudomembrane. • Lesions usually resolve in 7 to 10 days but are often recurrent; larger ulcers may last several weeks to months and can leave a temporary scar. • It is often difficult to eat due to the discomfort of chewing food and the ensuing pain from scraping the food against the lesion. When located near the soft palate or esophagus, it becomes difficult to swallow due to odynophagia. Pain from aphthae on the lip or tongue can also cause patients to limit their speech. 

GENERAL CONSIDERATIONS Aphthous stomatitis, recurrent aphthous ulcers (RAUs), or canker sores is a common condition, affecting 1% to 78% of the population, depending on country and on data from clinical examination or information from the patient’s history.1 RAU is an idiopathic multifactorial disorder that can cause significant morbidity (Fig. 147.1). Although usually self-limited, in some individuals recurrence can appear continuous. Inflammatory bowel disease (IBS), celiac disease, systemic lupus erythematosus, AIDS, and Behçet’s syndrome are systemic disorders associated with RAUs. Many people mistakenly identify RAUs as herpes simplex, although there is an uncommon form, known as herpetiform RAU, consisting of clusters of aphthae less than 1 mm in diameter (Fig. 147.2). Table 147.1 lists several conditions included in the differential diagnosis of RAU.2

*Previous edition contributor

1114

Stress, 1116 Nutrient Deficiency, 1116 Quercetin, 1116 Deglycyrrhizinated Licorice, 1116 Therapeutic Approach, 1116 Diet, 1116 Nutritional Supplements, 1116 Botanical Medicines, 1117

The etiology, based on studies of initiating factors, appears to be related to genetics, food sensitivities (especially gluten sensitivity), nutrient deficiency, and hormonal changes.3 These factors unify the key underlying feature of RAU—genetic predisposition and dysregulation of the immune system in the oral mucosa. Family history is positive in up to 40% of patients.4 Genetic risk factors that modify individual susceptibility to RAU include HLA alleles and DNA polymorphisms, especially those related to alterations in the metabolism of interleukins, interferon (IFN)-c and tumor necrosis factor (TNF)-a.5 Histologically, RAU consists of mucosal ulcerations with mixed inflammatory cell infiltrates. T-helper cells predominate in the preulcerative and healing phases, whereas T-suppressor cells predominate in the ulcerative phase. Other findings associated with immune dysregulation include: • Lymphomononuclear infiltrate and hemagglutination antibodies against oral mucosa • Reduced response of lymphocytes to mitogens • Circulating immune complexes • Alterations in natural killer (NK) cell activity • Increased adherence of neutrophils • Release of tumor necrosis factor-alpha (TNF-α) • Significant involvement of mast cells in the pathogenesis of RAU • Reduced levels and function of regulatory T cells in aphthae • Reduced expression of heat shock protein 27 and interleukin 10 in lesions6 • Elevated salivary and serum cortisol7 • Elevated Toll-like receptor activity8 • Oxidative stress as measured by glutathione and malonidialdehyde9 

THERAPEUTIC CONSIDERATIONS Allergies and Environmental Factors The oral cavity is obviously the first site of contact for ingested and many inhaled allergens. The histological appearance of the lesions and the association of RAU with increased serum antibodies to food antigens and atopy suggest that an allergic reaction may be involved.10

CHAPTER 147 

Fig. 147.1  Aphthous stomatitis. (Retrieved from https://www.istockphoto .com/photo/lip-with-aphthous-stomatitis-gm472584972-63480929)

Aphthous Stomatitis

1115

• D  ichromate • Sorbic acid Elimination of allergens usually brings significant improvement and in many cases complete resolution.15 Local, chemical, or physical trauma often initiates aphthae in susceptible individuals (pathergy). Conclusive evidence is lacking to support the role of an infectious etiology, including herpes simplex virus, human herpes virus, varicella zoster virus, cytomegalovirus, and Helicobacter pylori.16,17 Approximately 66% of HIV-positive individuals have herpetiform ulcers and RAUs, which must be differentiated from those caused by antiretroviral medications and bacterial, viral, or fungal infections.18 RAU can result from a T cell–mediated response to antigens of Streptococcus sanguis that cross-react with heat-shock proteins. One controlled study has shown a statistically significant increase in RAU in subjects taking nonsteroidal anti-inflammatory drugs (NSAIDs).19 Oral hygiene products, chewing gum, candy, acidic foods, and walnuts have been associated with RAU. The avoidance of toothpaste containing sodium lauryl sulfate may be helpful.20,21 Two studies of traditional Chinese herbal formulas added to toothpastes have shown significant benefit for RAU patients.22,23 

Gluten Sensitivity

Fig. 147.2  Herpetiform recurrent aphthous stomatitis.

TABLE 147.1  Differential Diagnosis for

Recurrent Aphthous Stomatitis • • • • • • • • • • • • • • •

Herpes zoster Pemphigus vulgaris Candidiasis Acute cutaneous lupus erythematosus Allergic contact dermatitis Cancers of the oral mucosa Cicatricial pemphigoid Erythema multiform Irritant contact dermatitis Langerhans cell histiocytosis Lichen planus Linear IgA dermatosis Paraneoplastic pemphigus Sweet syndrome Reactive arthritis

• C ontact stomatitis • O  ral mucosal manifestations of GI disease • Oral mucosal manifestations of hand-foot-mouth disease • Oral manifestations of hematological disease • Drug-induced bullous disorders • Drug-induced lupus erythematosus • Drug-induced pemphigus • IgA pemphigus • Sarcoidosis • Pediatric syphilis • Morsicatio buccalis • Traumatic eosinophilic ulcer • Steven-Johnson syndrome

GI, Gastrointestinal; IgA, immunoglobulin A.

Furthermore, immunoglobulin E–bearing lymphocytes are significantly increased in aphthous lesions, and mast cells are increased in tissue sections from prodromal stages of recurrent ulcers.11 Mast cell degranulation plays an important role in the production of the aphthous lesion.12 An elimination diet has been shown to have good therapeutic results.13 The allergen is not necessarily a food. Additional allergens inducing RAU are14: • Benzoic acid • Cinnamaldehyde • Nickel • Parabens

Considerable evidence indicates that sensitivity to gluten is associated with RAU. The incidence of RAU is increased in patients with celiac disease.24-27 Jejunal biopsy of 33 patients with RAU showed 8 to have the villous atrophy typical of celiac disease, along with histological signs of immunological reactions to food antigens.24 The remaining patients also exhibited these types of signs but to a lesser degree. Although villous atrophy is a prerequisite for the diagnosis of celiac disease, gluten sensitivity may take other forms: Gluten may act directly on the oral mucosa or produce functional changes in the small intestine by immunological or other mechanisms that are distinct from those causing the characteristic abnormalities of celiac disease.26 An underlying gluten-sensitive enteropathy could also contribute to nutritional deficiencies. Withdrawing gluten from the diet results in complete remission of RAU in patients with celiac disease and some improvement in others.24-27 Even in the absence of villous atrophy, gluten sensitivity can produce RAU. For example, in one small study, three of four gluten-sensitive patients identified by positive antibodies to alpha-gliadin but with normal small intestinal biopsy responded dramatically to a gluten-free diet.28 We recommend ruling out celiac disease by measuring tissue transglutaminase and reticulin antibodies in any patient presenting with RAU. 

Dietary Factors A study of students at Beijing University of Chinese Medicine used a questionnaire to investigate the occurrence of RAU.29 Researchers found that bedtime later than 11 pm, dry mouth, constant thirst, and frequent intake of carbonated beverages were independent risk factors of RAU. The data also supported avoidance of fried food, sweet drinks, pineapple, and spicy foods, moderate intake of nuts, and cautioned intake of fruits. 

Mechanical Injuries In many RAU patients, lesions appear on the oral mucosa shortly after mechanical trauma to the area.30 Accidental bites of the mucosal tissue, hard brushing of the mucosal tissue, or injuries from rigid solid foods can lead to posttraumatic aphthae. 

Hormonal Changes RAU may occur or increase in severity during the luteal phase of the menstrual cycle. A case which responded to implants of low doses of testosterone was published in the British Medical Journal in 1981.31 

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SECTION 6 

Diseases

Stress Stress is often a precipitating factor in RAU, suggesting a breakdown in normal host protective factors.32 Elevated urinary and salivary cortisol levels demonstrate a significant correlation as markers for stress in patients with RAU.33 

Nutrient Deficiency The oral cavity is often the first place that nutritional deficiency becomes visible to the physician because of the high turnover rate of the mucosal epithelium. Although several nutrient deficiencies can lead to aphthous stomatitis, thiamin appears to be the most significant. In one study seeking to examine whether thiamin deficiency is associated with RAU, the level of transketolase (a thiamin-dependent enzyme) was determined in 70 patients with RAU and 50 patients from a control group.34 Low levels of transketolase were found in 49 of 70 patients with RAS, compared with only 2 of 50 among the controls. These results clearly demonstrate an association between low levels of thiamin and RAU. Several other studies show that nutrient deficiencies are much more common in RAU sufferers than in others. For example, a study of 330 patients with recurrent aphthous stomatitis (RAS) found that 47 (14.2%) were deficient in iron, folate, vitamin B12, or a combination of those nutrients.35 In another study of 60 patients, 28.2% were deficient in thiamin, riboflavin, or pyridoxine.36 When the patients’ deficiencies were corrected, the majority had complete remission. Lower dietary intake of folate and vitamin B12 is common in persons with RAU, and treatment with 1000 mcg per day has shown benefit regardless of serum vitamin B12 levels.37 Additional studies have shown similar deficiency rates for the same nutrients and equally positive responses to supplementation.38 Zinc supplementation has also been shown to be helpful. A pilot study showed a significant association between zinc deficiency and RAU. In the study, 28% of 25 subjects with RAU had zinc deficiency compared with 4% of 25 healthy controls.39 In one double-blind study, 40 patients with RAU were given either zinc sulfate (220 mg providing 50 mg of elemental zinc) or a placebo once daily for 1 month.40 Results showed that the levels of serum zinc before treatment were below the normal value in 42.5% of the patients with RAU. After 1 month of zinc therapy, the aphthae reduced and did not reappear for 3 months. Low nutrient status may explain why patients with RAU have an increased oxidant/antioxidant ratio in comparison with healthy controls. A small study of adolescents showed a reduction in the incidence of RAU and associated pain from 2000 mg per day of ascorbate.41 In another study, superoxide dismutase, glutathione peroxidase (GSHPx), and catalase (CAT) activities as well as and malondialdehyde (MDA) and antioxidant potential (AOP) levels were measured in plasma and erythrocytes from 22 patients with RAS and 23 controls.42 Researchers found decreased CAT and GSHPx activities and AOP levels in the erythrocytes as well as decreased AOP and increased MDA plasma levels in patients with RAU in comparison with control subjects. This study clearly demonstrated that enzymatic and nonenzymatic antioxidant defense systems are impaired in patients with RAU. In an Italian study, a multivitamin, a proprietary topical drug, and the long-lasting anesthetic ropivacaine were used separately and in combination for patients with RAU.43 Researchers determined the combination of the three agents was a reliable therapy for patients with oral aphthosis, providing significant reduction of pain and length of healing time. Oral microbiome research suggests that an imbalance of the oral mucosal microbiome, rather than individual infectious pathogens, may play a role in initiating RAU. The findings raise the question of whether the presence of a lesion alters the microbiota of the oral cavity

or a change in microbiota triggers the development of aphthosis. There is likely interplay between the two. One study compared the buccal microbiota of patients with RAU with control subjects and concluded that differences in bacteria were related to the presence of lesions during sampling. Bacterial diversity in the oral microbiota were similar in patients with RAU and controls.44 Another study found that RAU is associated with dysbiosis of the mucosal and salivary microbiota and identified associations between RAU risk and decreased Streptococcus salivarius and increased Acinetobacter johnsonii.45 

Quercetin Quercetin is known to inhibit mast cell degranulation, basophil histamine release, and the formation of other mediators of inflammation.46 The antiallergy drug disodium cromoglycate, a compound similar in structure and function to quercetin, has been shown to be effective in the treatment of RAU, resulting in more ulcer-free days and mild symptomatic relief.47 Other flavonoids (acacetin, apigenin, chrysin, and phloretin but not catechin, flavone, morin, rutin, or taxifolin) have also shown antiallergy effects similar to those of disodium cromoglycate.46 

Deglycyrrhizinated Licorice Deglycyrrhizinated licorice (DGL) may be effective in promoting the healing of RAU. In one study, 20 patients were instructed to use a solution of DGL as a mouthwash (200 mg of powdered DGL dissolved in 200 mL of warm water) four times daily.48 Of the 20 patients, 15 (75%) experienced 50% to 75% improvement within 1 day, followed by complete healing of the ulcers by the third day. DGL in tablet form may be more convenient and effective. Topical preparations containing the solid extract of licorice root are also available (e.g., Canker Cover made by Quantum Health). A randomized controlled trial showed significant efficacy of a paste containing Myrtus communis (myrtle) for RAU when applied four times daily for 6 days.49 

THERAPEUTIC APPROACH Data suggests that no single factor is solely responsible for the initiation of aphthous lesions. However, an underlying genetic tendency may be present, the expression of which is facilitated by multiple factors. Considerable evidence suggests that gluten sensitivity may be a contributing factor in some patients. In addition, nutrient deficiencies must be corrected and anti-inflammatory nutrients prescribed. A randomized controlled trial showed significant benefit from individualized homeopathic treatment, when the medicine was administered in 6 c potency as oral liquid for two doses only.50

Diet The patient’s diet should be free of known allergens and all gluten sources if gluten sensitivity is present. Fried foods, carbonated sodas, and sweet drinks should be avoided. Acidic foods (tomatoes, citrus, pineapple) should also be avoided if found to trigger aphthae. 

Nutritional Supplements • • • •

 igh-potency multivitamin and mineral formula H Calcium ascorbate: 2000 mg per day Sublingual vitamin B12: 1000 mcg per day Zinc lozenges with Echinacea and Vitamin C (available OTC, containing 23 mg of zinc citrate/gluconate) • “Kanka” liquid treatment for canker sores (an OTC product containing zinc oxide and benzocaine) 

CHAPTER 147 

Aphthous Stomatitis

Botanical Medicines

REFERENCES

• D  eglycyrrhizinated licorice (DGL): one to two 380-mg chewable tablets 20 minutes before meals • Topical licorice root preparations applied as needed

See www.expertconsult.com for a complete list of references.

1117

REFERENCES 1. Safadi RA. Prevalene of recurrent aphthous ulceration in Jordanian dental patients. BMC Oral Health. 2009;9:31. 2. Femiano F, Lanza A, Buonaiuto C, et al. Guidelines for diagnosis and management of aphthous stomatitis. Pediatr Infectious Dis J. 2007;26(8):728– 732. 3. Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp (Warsz). 2014;62(3):205–215. 4. Chavan M, Jain H, Diwan N, et al. Recurrent aphthous stomatitis: a review. J Oral Pathol Med. 2012;41(8):577–583. 5. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003;134:200–207. 6. Miyamoto Jr NT, Borra RC, Abreu M, et al. Immune-expression of HSP27 and IL-10 in recurrent aphthous ulceration. J Oral Pathol Med. 2008;37(8):462–467. 7. Albanidou-Farmaki E, Poulopoulos AK, Epivatianos A, et al. Increased anxiety level and high salivary and serum cortisol concentrations in patients with recurrent aphthous stomatitis. Tohoku J Exp Med. 2008;214(4):291–296. 8. Borra RC, de Mesquita Barros F, de Andrade Lotufo M, et al. Toll-like receptor activity in recurrent aphthous ulceration. J Oral Pathol Med. Mar. 2009;38(3):289–298. 9. Arikan S, Durusoy C, Akalin N, et al. Oxidant/antioxidant status in recurrent aphthous stomatitis. Oral Dis. 2009;15(7):512–515. 10. Wilson CWM. Food sensitivities, taste changes, aphthous ulcers and atopic symptoms in allergic disease. Ann Allergy. 1980;44:302–307. 11. Bays RA, Hamerlinck F, Cormane RH. Immunoglobulin-bearing lymphocytes and polymorphonuclear leukocytes in recurrent aphthous ulcers in man. Arch Oral Biol. 1977;22:147–153. 12. Wray D, Vlagopoulos TP, Siraganian RP. Food allergens and basophil histamine release in recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol. 1982;54:388–395. 13. Hay KD, Reade PC. The use of an elimination diet in the treatment of recurrent aphthous ulceration of the oral cavity. Oral Surg Oral Med Oral Pathol. 1984;57:504–507. 14. Nolan A, Lamey PJ, Milligan KA. Recurrent aphthous ulceration and food sensitivity. J Oral Pathol Med. 1991;20:473–475. 15. Wright A, Ryan FP, Willingham SE, et al. Food allergy or intolerance in severe recurrent aphthous ulceration of the mouth. Br Med J (Clin Res Ed). 1986;292(6530):1237–1238. 16. Ghodratnama F, Wray D, Bagg J. Detection of serum antibodies against cytomegalovirus, varicella zoster virus and human herpesvirus 6 in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 1999;28(1):12–15. 17. Mansour-Ghanaei F, Asmar M, Bagherzadeh AH, et al. Helicobacter pylori infection in oral lesions of patients with recurrent aphthous stomatitis. Med Sci Monit. Dec. 2005;11(12):CR576–CR579. 18. MacPhail LA, Greenspan D, Feigal DW, et al. Recurrent aphthous ulcers in association with HIV infection: description of ulcer types and analysis of T-lymphocyte subsets. Oral Surg Oral Med Oral Pathol. 1991;71(6):678– 683. 19. Hasan AA, Ciancio S. Association between ingestion of nonsteroidal anti-inflammatory drugs and the emergence of aphthous-like ulcers. J Int Acad Periodontol. 2009;11(1):155–159. 20. Shim YJ, Choi JH, Ahn HJ, Kwon JS. Effect of sodium lauryl sulfate on recurrent aphthous stomatitis: a randomized controlled clinical trial. Oral Dis. 2012;18(7):655–660. 21. Altenburg A, El-Haj N, Micheli C, et al. The treatment of chronic recurrent oral aphthous ulcers. Dtsch Arztebl Int. 2014;111(40):665–673. 22. Yang Y, Zhang T, Dong Z, et al. Short-term efficacy of Pudilan Keyanning toothpaste in treatment of minor recurrent aphthous ulcers. Evid Based Complement Alternat Med. 2016;2016:9125327. 23. Liu XS, Guan XB, Chen RY, et al. Repurposing of Yunnan Baiyao as an alternative therapy for minor recurrent aphthous stomatitis. Evid Based Complement Alternat Med. 2012;2012:6. https://doi.org/ 10.1155/2012/284620.284620.

24. Ferguson R, Basu MK, Asquith P, et al. Jejunal mucosal abnormalities in patients with recurrent aphthous ulceration. Br Med J. 1976;1:11–13. 25. Ferguson MM, Wray D, Carmichael HA, et al. Celiac disease associated with recurrent aphthae. Gut. 1980;21:223–226. 26. Wray D. Gluten-sensitive recurrent aphthous stomatitis. Dig Dis Sci. 1981;26:737–740. 27. Besu I, Jankovic L, Magdu IU, et al. Humoral immunity to cow’s milk proteins and gliadin within the etiology of recurrent aphthous ulcers? Oral Dis. 2009;15(8):560–564. 28. O’Farrelly C, O’Mahony D, Graeme-Cook F, et al. Gliadin antibodies identify gluten-sensitive oral ulceration in the absences of villous atrophy. J Oral Pathol Med. 1991;20:476–478. 29. Shi L, Wan K, Tan M, et al. Risk factors of recurrent aphthous ulceration among university students. Int J Clin Exp Med. 2015;8(4):6218–6223. 30. Polanska B, Niemczuk M, Augustyniak D, et al. Plasma neutrophil elastase in children with recurrent aphthous stomatitis. Centr Eur J Immunol. 2006;31:15–17. 31. Misra R, Anderson DC. Treatment of recurrent premenstrual orogenital aphthae with implants of low doses of testosterone. BMJ. 1989;299(6703):834. 32. Ship II , Merritt AD, Stanley HR. Recurrent aphthous ulcers. Am J Med. 1962;32:32–43. 33. Karthikeyan P, Aswath N. Stress as an etiologic co-factor in recurrent aphthous ulcers and oral lichen planus. J Oral Sci. 2016;58(2):237– 240. 34. Haisraeli-Shalish M, Livneh A, Katz J. Recurrent aphthous stomatitis and thiamine deficiency. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:634–636. 35. Wray D, Ferguson MM, Hutcheon AW, et al. Nutritional deficiencies in recurrent aphthae. J Oral Path. 1978;7:418–423. 36. Nolan A, McIntosh WB, Allam BF, et al. Recurrent aphthous ulceration. Vitamin B1, B2, and B6 status and response to replacement therapy. J Oral Pathol Med. 1991;20:389–391. 37. Carrozzo M. Vitamin B12 for the treatment of recurrent aphthous stomatitis. Evid Based Dent. 2009;10(4):114–115. 38. Wray D, Ferguson MM, Mason DK, et al. Recurrent aphthae: treatment with vitamin B12, folic acid, and iron. Br Med J. 1975;2:490–493. 39. Ozler GS. Zinc deficiency in patients with recurrent aphthous stomatitis: a pilot study. J Laryngol Otol. 2014;128(6):531–533. 40. Orbak R, Cicek Y, Tezel A, et al. Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J. 2003;22:21–29. 41. Yasui K, Kurata T, Yashiro M, et al. The effect of ascorbate on minor recurrent aphthous stomatitis. Acta Paediatr. Dec. 2009;10:442–445. 42. Cimen MY, Kaya TI, Eskandari G, et al. Oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Clin Exp Dermatol. 2003;28: 647–650. 43. Basparini G, Saponaro G, Gasparini D, et al. The use of ropivacaine in therapeutic treatment of oral aphthosis. Biomed Res Int. 2018;1868254. 44. Bankvall M, Sjoberg F, Gale G, et al. The oral microbiota of patients with recurrent aphthous stomatitis. J Oral Microbiol. 2014;6. 45. Kim Y, Choi YS, Baek KJ, et al. Mucosal and salivary microbiota associated with recurrent aphthous stomatitis. BMC Microbiol. 2016;16:57. 46. Pearce FL, Befus AD, Bienenstock J. Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol. 1984;73:819–823. 47. Kowolik MJ, Muir KF, MacPhee IT. Di-sodium cromoglycate in the treatment of recurrent aphthous ulceration. Br Dent J. 1978;144:384–389. 48. Das SK, Das V, Gulati AK, et al. Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India. 1989;37:647. 49. Babaee N, Mansourian A, Momen-Heravi F, et al. The efficacy of a paste containing Myrtus communis (myrtle) in the management of recurrent aphthous stomatitis: a randomized controlled trial. Clin Oral Investig. 2010;14(1):65–70. 50. Mousavi F, Mojaver YN, Asadzadeh M, et al. Homeopathic treatment of minor aphthous ulcer: a randomized, placebo-controlled clinical trial. Homeopathy. 2009;98(3):137–141.

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148 Asthma John Nowicki, ND, and Michael T. Murray*, ND

OUTLINE Diagnostic Summary, 1118 General Considerations, 1118 Major Categories, 1118 Diagnostic Considerations, 1119 Causes, 1119 Mediators, 1119 Lipoxygenase Products, 1120 Autonomic Nervous System, 1121 Adrenal Gland, 1121 Vaccinations, 1121 Environmental Toxins, 1121 Mold, 1122 Drugs, 1122 Therapeutic Considerations, 1122

DIAGNOSTIC SUMMARY • R  ecurrent attacks of dyspnea, cough, and expectoration of tenacious mucoid sputum • Prolonged expiration phase with generalized wheezing and musical rales • Eosinophilia, increased serum immunoglobulin E (Ig E), positive food/inhalant allergy tests 

GENERAL CONSIDERATIONS Bronchial asthma is a hypersensitivity disorder characterized by bronchospasm, mucosal edema, and excessive excretion of viscous mucus that can lead to ventilatory insufficiency. Asthma affects approximately 7% of the population of the United States and causes 4210 deaths per year. Although it occurs at all ages, it is most common in children below age 10. There is a 2:1 male:female ratio in children, which equalizes by the age of 30.1 Major factors involved in asthma include the following: • Hypersensitivity of the airways • Beta-adrenergic blockade • Cyclic nucleotide imbalance in airway smooth muscle • Release of inflammatory mediators from mast cells The incidence of asthma is rising rapidly in the United States, especially in children. Reasons often given to explain the rise in asthma include the following:

*Previous edition contributor

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General, 1122 Diet, 1123 Nutrition, 1124 Botanical Medicines, 1127 Acupuncture and Acupressure, 1128 Therapeutic Approach, 1129 Environment, 1129 Diet, 1129 Supplements, 1129 Botanical Medicines, 1129 Counseling, 1130 Acupuncture and Acupressure, 1130 In Acute Attack, 1130

• I ncreased stress on the immune system due to factors such as greater chemical pollution in the air, water, insect allergens from mites and cockroaches, and food • Earlier weaning and earlier introduction of solid foods to infants • Food additives • Higher incidence of obesity2 • Genetic manipulation of plants, resulting in food components with greater allergenic tendencies In addition, multiple genetic variables may make certain individuals more susceptible to asthma. For example, researchers have demonstrated that a deficiency in the glutathione S-transferase M1, a gene involved in response to oxidative stress, may also make those with this deletion more susceptible to asthmatic attacks, thus supporting the need for antioxidant therapy in these individuals.3 The ADAM33 gene on chromosome 20p13 has been linked to the pathogenesis involved in airway remodeling (see later mediators section) and is probably a factor in corticosteroid resistance in some patients with asthma.4 Other research teams have identified genes on chromosomes 7 and 12 as probable players in the pathogenesis of asthma.5,6

Major Categories Asthma has typically been divided into two categories: extrinsic and intrinsic. Extrinsic or atopic asthma is generally considered an immunologically mediated condition with a characteristic increase in serum IgE. Intrinsic asthma is associated with a bronchial reaction that is due not to antigen–antibody stimulation but rather such factors as chemicals, cold air, exercise, infection, agents that activate the alternative complement pathway, and emotional upset.

CHAPTER 148  Asthma is often clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEV1), and peak expiratory flow rate. 

Diagnostic Considerations The U.S. National Asthma Education and Prevention Program (NAEPP) guidelines for the diagnosis and management of asthma (Table 148.1) state that a diagnosis of asthma begins by assessing whether any of the indicators is present: • Wheezing—high-pitched whistling sounds on expiration—especially in children (Lack of wheezing and a normal chest examination do not exclude asthma.) • History of any of the following: • Cough, particularly worse at night • Recurrent wheeze • Recurrent difficulty in breathing • Recurrent chest tightness • Symptoms occur or worsen in the presence of: • Exercise • Viral infection • Animals with fur or hair • House dust mites (in mattresses, pillows, upholstered furniture, carpets) • Mold • Smoke (tobacco, wood) • Pollen • Changes in weather • Strong emotional expression (laughing or crying hard) • Airborne chemicals or dusts • Menstrual cycles • Symptoms that occur or worsen at night, awakening the patient Spirometry plays a central role in the management of asthma and should be performed at the time of initial diagnosis, after treatment is initiated and symptoms are stabilized, whenever control of symptoms deteriorates, and every 1 or 2 years on a regular basis. 

Asthma

1119

Causes Asthma is caused by a complex interaction of environmental and genetic factors. The strongest risk factor for developing asthma is a history of atopic disease. The presence of atopic dermatitis increases the risk of asthma by three- to fourfold. Allergies and the response of the immune system are obviously involved in asthma.

Inflammation and Th1/Th2 Balance Imbalances in T-helper cell immune responses appear to be a fundamental mechanism of immunologically mediated airway inflammation. CD4+ T-helper cells are generally categorized into Th1 and Th2 cells. Via the release of interferons and interleukin 2, the Th1 pathway is increased in the immunological responses to cancer, multiple sclerosis, viruses, and type IV hypersensitivities. Th2 responses are related to increases in interleukins 4, 6, 9, and 13; IgE, eosinophilia; and activated B-cell humoral immunity. Clinical conditions that reflect increased Th2 responses include asthma and atopic syndromes as well as allergies. Research involving asthmatic subjects demonstrates a normal Th1 gene expression but a constant upregulation of Th2-specific genes, leading to Th2 predominance.7 Although it is unclear what the cause of this exaggerated Th2 response is in asthma, it seems that genetics, fungi, metal toxicities, nutrition, viruses, and pollution are factors in this upregulation (Fig. 148.1).8 The “hygiene hypothesis” is also gaining ground in the standard medical literature. It asserts that by minimizing exposure to infectious agents owing to lifestyle choices based on hygienic concerns, the dominance of Th2 immune responses to environmental allergens has been favored and thus also the probable encouragement of asthma and atopic diseases.9,10 

Mediators Both extrinsic and intrinsic factors involved primarily with Th2 imbalances trigger the cytokine-activated release of mast cell–derived chemical mediators. These mediators are responsible for bronchoconstriction, mucus production, and other signs and symptoms in the majority of cases. These mediators are either preformed within granules or generated from membrane-bound phospholipids. The preformed mediators include histamine, various chemotactic peptides such as eosinophilic chemolactic factor (ECF) and high-molecular-weight neutrophil

TABLE 148.1  National Asthma Education and Prevention Program (NEAPP) Classification of

Asthma Severity Before Treatment in Adults and Youths 12 Years and Oldera Component of Severity Symptoms Night-time awakenings

PERSISTENT Intermittent ≤2 days/week ≤2x/month

Mild

Moderate

Severe

>2 days per week but not daily

Daily

Throughout the day

3–4×/month

>1×/week but not nightly

Often 7×/week

≤days/week

>2 days per week but not > 1×/day

Daily

Several times per day

Interference with normal activity

None

Minor limitation

Some limitation

Extremely limited

Pulmonary function

Normal FEV1 between exacerbations; FEV1 ≥80% predicted; FEV1/FVC normal

FEV1 45 g/day), and moderate alcohol consumption (one to three glasses a day) was associated with a 139-mL-higher FEV1 and a 50% lower prevalence of chronic obstructive pulmonary disease versus diets that did not meet these intake requirements.57 Finally, one study of 607 asthma patients and 864 controls highlighted apples and moderate red wine consumption as sources of antioxidants that decreased asthma severity.62 Dietary intake of soy foods may be helpful because the soy isoflavone genistein is associated with reduced severity of asthma. Although this effect may be due to some antioxidant action, studies have also shown that genistein is able to block eosinophil leukotriene C(4) synthesis and inhibit the pathway of NF-κB and tumor necrosis factor-α (TNF-α) in patients with asthma.63–65 

Food Allergy Many studies have indicated that food allergies play an important role in asthma (see Chapter 14).66–70 Adverse reactions to food may be immediate or delayed. Double-blind food challenges in children have

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SECTION 6 

Diseases

shown that immediate-onset sensitivities are usually due (in decreasing order of frequency) to egg, fish, shellfish, nuts, and peanuts, whereas the foods most commonly associated with delayed onset include (in decreasing order of frequency) milk, chocolate, wheat, citrus, and food colorings.68 Elimination diets have been successful in identifying allergens and treating asthma and are a particularly valuable diagnostic and therapeutic tool in infants.71 Elimination of common allergens during infancy (first 2 years) has been shown to reduce allergic tendencies in high-risk children (e.g., strong familial history).72 

Breastfeeding Many studies have demonstrated the protective effect of breastfeeding in the prevention of asthma. One study examined the association of breastfeeding and the presence of chronic respiratory symptoms among 5182 Brazilian schoolchildren 7 to 14 years of age. Ninety percent of the mothers in this population had breastfed their infants. After adjusting for potential confounding factors, these researchers revealed that children who had not been breastfed were more likely to have a medical diagnosis of asthma.73 One Iraqi study additionally showed that the vitamin C content of breast milk was significantly correlated with the maternal intake of vitamin C; low vitamin C intake by the mother translates to low intake by the child, thus leaving him or her more susceptible to oxidative stress.74 The Canadian Asthma Primary Prevention study collected 2 years of data in which researchers chose 545 infants who were considered at high risk for asthma on the basis of a history of familial atopy. These children were broken down into control and intervention groups. The interventions included (1) measures to control house dust; (2) recommendations for avoidance of pets, environmental tobacco smoke, and day care during the first year; and (3) only breastfeeding or the use of partially hydrolyzed whey formula until at least the age of 4 months. At 1 year of age, the risk of asthma was significantly reduced by 34%. At 2 years of age, significantly fewer children had asthma in the intervention group than in the control group (16.3% vs. 23%), and 60% fewer of those in the intervention group had persistent asthma. A 90% reduction in recurrent wheeze was seen in the intervention group compared with the control group.75 Studies like these are quite useful to elucidate the multitude of changes necessary to affect multifactorial diseases like asthma in an effective manner. 

Antibiotics, Probiotics, and Mucosal IgA In a combined analysis of seven studies involving more than 12,000 youngsters, researchers at the University of British Columbia found that those prescribed antibiotics before their first birthday were more than twice as likely as untreated kids to develop asthma.76 Additionally, if they had multiple courses of antibiotics, it bumped up the risk even higher—16% for every course of the drugs taken before age 1. There are a couple of explanations for this association between antibiotic use and asthma. One is that antibiotics contribute to a state of “excess hygiene,” leading to a reduced exposure to microbes. This, in turn, creates an oversensitive immune system, mounting an over-the-top allergic reaction to pollen and dust mites and ultimately resulting in asthma. The second explanation is that antibiotics have a negative effect on the normal flora of the gastrointestinal tract and respiratory passages. Some studies have shown that giving probiotics (active cultures of Lactobacillus and Bifidobacterium species) lowers the risk of atopic allergic diseases like asthma and eczema. Some of this protective effect may be mediated by mucosal IgA, which participates in antigen elimination. In a cohort of 237 allergy-prone infants given a combination of four probiotic strains or placebo, it was shown that supplementation with probiotics increased fecal IgA and calprotectin while

reducing inflammatory markers (e.g., α1-antitrypsin and TNF-α).77 In infants with a high fecal IgA concentration at the age of 6 months, the risk of having any allergic disease or any IgE-associated (atopic) disease before the age of 2 years was cut by nearly 50%. High intestinal IgA in early life is associated with minimal intestinal inflammation and indicates a reduced risk for IgE-associated allergic diseases. 

Vegan Diet A long-term trial of a vegan diet (elimination of all animal products) provided significant improvement in 92% of the 25 treated patients who completed the study (9 dropped out).78 Improvement was determined by a number of clinical variables, including vital capacity, FEV1, and physical working capacity, as well as by biochemical indices such as haptoglobin, IgM, IgE, cholesterol, and triglyceride levels in the blood. The researchers also found a reduction in the vulnerability to infection. Importantly, although 71% of the patients responded within 4 months, 1 year of therapy was required before the 92% level was reached. The diet excluded all meat, fish, eggs, and dairy products. Drinking water was limited to spring water (chlorinated tap water was specifically prohibited). Coffee, ordinary tea, chocolate, sugar, and salt were also excluded. Herbal spices were allowed, and water and herbal teas were allowed up to 1.5 L/day. Vegetables eaten freely were lettuce, carrots, beets, onions, celery, cabbage, cauliflower, broccoli, nettles, cucumber, radishes, Jerusalem artichokes, and all beans except soybeans and green peas. Potatoes were allowed in restricted amounts. A number of fruits were also eaten freely: blueberries, cloudberries, raspberries, strawberries, black currants, gooseberries, plums, and pears. Apples and citrus fruits were not allowed, and grains were either restricted or eliminated. The beneficial effects of this dietary regimen are probably related to three areas: • Elimination of food allergens • Altered prostaglandin metabolism • Increased intake of antioxidant nutrients and magnesium In regard to altered prostaglandin metabolism, the avoidance of dietary sources of arachidonic acid (derived from animal products) appears to be significant. The prostaglandins and leukotrienes derived from arachidonic acid contribute significantly to the allergic reaction in asthma. The decreased availability of arachidonic acid as a substrate of these inflammatory compounds appears to explain some aspects of the efficacy of the vegan diet. The benefits of altering prostaglandin metabolism are further discussed later, as is the role of increased dietary antioxidants in preventing asthma. Aside from the patients’ improvement in health from the vegan diet, there was a significant reduction in healthcare costs (the patients had been receiving corticosteroids and other drugs and therapies for an average of 12 years), and according to the authors, patients changed their attitudes in terms of taking greater responsibility for their own health. 

Nutrition

Omega-3 Fatty Acids Epidemiological studies have shown that children who eat fish more than once a week have one-third the risk of asthma of children who do not eat fish regularly.79 Several clinical studies have shown that increasing the intake of omega-3 fatty acids through supplementation with fish oils containing eicosapentaenoic acid and docosahexaenoic acid offers significant benefits in asthma, as noted by improvements in airway responsiveness to allergens as well as improvements in respiratory function.80,81 These benefits are related to an increased ratio of omega-3 to omega-6 fatty acids in cell membranes, thereby reducing

CHAPTER 148  the availability of arachidonic acid. In particular, the ingestion of omega-3 fatty acids leads to a significant shift in leukotriene synthesis from the extremely inflammatory 4-series to the less inflammatory 5-series leukotrienes. This shift is directly related to improvements in asthma symptoms.82 The benefits may take as long as 1 year to become apparent because it seems to take time to turn over cellular membranes in favor of the omega-3 fatty acids. 

Tryptophan Metabolism and Pyridoxine Supplementation Children with asthma have been shown to have a metabolic defect in tryptophan metabolism and reduced platelet transport for serotonin.83,84 Tryptophan is converted to serotonin, a known bronchoconstricting agent in asthmatics. High serotonin levels in the blood and sputum are common findings in patients with asthma and are reflected by an elevated urinary level of 5-hydroxyindoleacetic acid (5-HIAA), the breakdown product of serotonin. The levels of 5-HIAA in the urine correlate well with the severity of asthmatic symptoms. Double-blind clinical studies have shown that patients benefit from either a tryptophan-restricted diet83 or pyridoxine supplementation84,85 to correct the blocked tryptophan metabolism. Pyridoxine may also be of direct benefit to patients with asthma. In one study, plasma and erythrocyte pyridoxal phosphate levels in 15 adult patients with asthma were significantly lower than in 16 controls.84 Oral supplementation with 50 mg of pyridoxine twice daily to seven of the patients failed to produce a substantial elevation of these low levels. However, all patients reported a dramatic decrease in the frequency and severity of wheezing as well as asthma attacks while taking the supplements. In a study of 76 children with asthma, pyridoxine at a dosage of 200 mg daily produced significant reductions in symptoms and in dosages of bronchodilators and corticosteroids. However, a double-blind study failed to demonstrate any significant improvement with vitamin B6 supplementation in patients who depended on steroids to control symptoms.86 Although vitamin B6 supplementation may not help patients on steroids, it is definitely indicated in patients with asthma being treated with the drug theophylline. Theophylline significantly depresses pyridoxal-5-phosphate levels.87 In addition, another study has shown that vitamin B6 supplementation can significantly reduce the typical side effects of theophylline (e.g., headaches, nausea, irritability, sleep disorders).88 

Antioxidants The substantial increase in the prevalence of asthma over the past 20 years can be partially explained by the reduced dietary intake of antioxidant nutrients like beta-carotene and vitamins A, C, and E, as well as the mineral cofactors essential for antioxidant defense mechanisms, such as zinc, selenium, and copper.89 Patients undergoing acute asthmatic distress are known to have lowered serum total antioxidants.90 Genetic influences may also play a role in the need for antioxidants (see “General Considerations” earlier in the chapter).3 One study of 158 children with moderate to severe asthma revealed that supplementation of 50 mg/day of vitamin E and 250 mg/day of vitamin C conferred significant protection against ozone-induced reductions in pulmonary function.91 Antioxidants are thought to provide important defense mechanisms for maintaining the redox state of the lungs. This protection is significant because oxidizing agents can both stimulate bronchoconstriction and increase hyperactivity to other agents. Asthma appears to be another disease process that is influenced greatly by antioxidant mechanisms. Analgesics like acetaminophen, known to deplete antioxidant levels such as glutathione in animals, should be used with caution in asthmatic patients.92 

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Vitamin C Vitamin C is the major antioxidant substance present in extracellular fluid lining the airway surfaces.93 Vitamin C intake in the general population appears to correlate with asthma, indicating that low vitamin C (in the diet and the blood) is an independent risk factor for asthma. In a survey of 771 persons with current asthma, 352 with former asthma, and 15,418 without asthma, lower vitamin C concentrations were observed among those with current or former asthma than those who had never had asthma.94 Children of smokers have a higher rate of asthma (cigarette smoke is known to deplete respiratory vitamins C and E levels), and symptoms of ongoing asthma in adults appear to be increased by exposure to environmental prooxidants and decreased by vitamin C supplementation.74 Nitrogen oxides are examples of oxidants that can arise from both endogenous and exogenous sources. Vitamin C has been shown to offer significant protection against nitrogen oxide damage in the lungs of animal models.95 Both treated and untreated patients with asthma have been shown to have significantly lower levels of ascorbic acid in serum and leukocytes.95 From a clinical perspective, it appears that patients with asthma have a higher need for vitamin C, with the majority of studies demonstrating significant improvements in respiratory measures and asthma symptoms as a result of supplementing the diet with 1 to 2 g of vitamin C daily.96 This dosage is recommended based on the increasing exposure to inhaled oxidants, along with the growing appreciation of the antioxidant function of vitamin C in the respiratory system. High-dose vitamin C therapy may also help asthma by lowering histamine levels.97 The importance of vitamin C as a natural antihistamine has emerged for several reasons, including concern over the safety of antihistamine medications and the recently recognized immune-suppressing effects of histamine. In the initial stages of an immune response, histamine amplifies the immune response by increasing capillary permeability and smooth muscle contraction, thus enhancing the flow of immune factors to the site of infection. Subsequently, histamine exerts a suppressive effect on the accumulated white blood cells (WBCs) in an attempt to contain the inflammatory response. Vitamin C prevents the secretion of histamine by WBCs and increases the detoxification of histamine. One study examined the antihistaminic effect of acute and chronic vitamin C administration and its effect on WBC (neutrophil) function in healthy men and women. In the chronic administration arm, 10 subjects ingested a placebo during weeks 1, 2, 5, and 6 and 2 g/day of vitamin C during weeks 3 and 4. Fasting blood samples were collected after the initial 2-week period (baseline) and at the end of weeks 4 and 6. Blood vitamin C levels rose significantly after vitamin C administration, whereas blood histamine levels fell by 38% during the weeks vitamin C was given. The ability of WNCs to move in response to an infection (chemotaxis) increased by 19% during vitamin C administration and fell 30% after vitamin C withdrawal. However, these changes were linked to histamine concentrations. Chemotaxis was greatest when histamine levels were the lowest. In the part of the study looking at the acute effects of vitamin C, blood histamine concentrations and chemotaxis did not change 4 hours after a single dose of vitamin C. This result suggests that vitamin C will lower blood histamine only if it is taken over time. Individuals prone to allergy or inflammation are encouraged to increase their consumption of vitamin C through supplementation.97 In a small study of patients with asthma and documented exercise-induced bronchoconstriction, the subjects participated in a randomized, placebo-controlled, double-blind crossover trial.98 They entered the study on their usual diets and were placed on either 2 weeks of ascorbic acid supplementation (1500 mg/day) or placebo, followed

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by a 1-week washout period, before crossing over to the alternative treatment. The ascorbic acid diet significantly reduced (P < 0.05) the maximum fall in postexercise FEV1 (–6.4 %) compared with the usual diet (–14.3%) and a placebo diet (–12.9%). Asthma symptom scores significantly improved on the ascorbic acid diet compared with the placebo and usual diets. Postexercise inflammatory mediators were also significantly lower with ascorbic acid supplementation. 

Flavonoids Flavonoids appear to be key antioxidants in the treatment of asthma. Various flavonoids, chief among them being quercetin, have been shown to inhibit the following99–102: • Histamine release from mast cells and basophils when stimulated by antigens and other ligands • Phospholipase A2 in neutrophils • Lipoxygenase • Anaphylactic contraction of smooth muscle • Phosphodiesterase in the lung (resulting in increased cAMP levels) • Biosynthesis of SRS-A • Calcium influx In addition, quercetin has both a vitamin C–sparing effect and a direct stabilizing effect on membranes, including mast cells. Flavonoid-rich extracts such as those from grape seed, pine bark, green tea, or Ginkgo biloba may prove even more helpful than quercetin in the treatment of asthma because of their enhanced bioavailability. In particular, the proanthocyanidins from grape seed or pine bark extracts appear to have an affinity for the lungs (for more information, see Chapter 106). In a randomized, placebo-controlled, double-blind study involving 60 subjects 6 to 18 years of age, a proprietary pine bark extract (Pycnogenol) significantly improved pulmonary function and asthma symptoms compared with placebo. Specifically, the Pycnogenol group was able to reduce or discontinue the use of rescue inhalers more often than the placebo group. There was also a significant reduction of urinary leukotrienes in the Pycnogenol group.103 In another study, a flavonoid preparation derived from purple passion fruit peel (PFP) was studied in a 4-week randomized, ­placebo-controlled, double-blind trial in asthma patients. The dosage of the PFP extract was 150 mg daily. The prevalence of wheeze, cough, and shortness of breath was reduced significantly in the group treated with PFP extract, whereas the placebo caused no significant improvement. PFP extract supplementation also resulted in a marked increase in FEV1, whereas placebo showed no effect.104 

Carotenes Carotenes are powerful antioxidants that may increase the integrity of the epithelial lining of the respiratory tract and act as substrates for lipoxygenase, possibly competing with arachidonic acid and thereby decreasing leukotriene formation.105 Some studies have shown that patients with asthma have reduced plasma antioxidant potential due to low whole-blood carotenoids (beta-carotene, lycopene, alpha-­ carotene, beta-cryptoxanthin, lutein/zeaxanthin),106 in particular low lycopene levels,107 thus making them more susceptible to the damaging effects of oxidative stress. Lycopene may emerge as the most useful supplemental carotenoid. In animal models of asthma, lycopene supplementation suppressed Th2 responses and reduced eosinophilic infiltrates in the bronchoalveolar lavage fluid, lung tissue, and blood as well as the number of mucus-secreting cells in the airways.108 In a proof-of-concept human study, asthmatic adults (n = 32) consumed a low-antioxidant diet for 10 days and then commenced a randomized crossover trial involving three 7-day treatment arms (placebo, tomato extract [45 mg lycopene per day], and tomato juice [45 mg lycopene per day]).109 With the consumption of a low-antioxidant diet, plasma carotenoid concentrations decreased, Asthma Control Score worsened, lung

function (FEV1 and FVC) decreased, and sputum neutrophils increased. Treatment with both tomato juice and extract reduced airway neutrophil influx. Treatment with tomato extract also reduced sputum neutrophil elastase activity. This short-term study indicates that antioxidant status, particularly in terms of carotenoids, modifies some parameters in asthma. There have been two double-blind studies of lycopene supplementation (30 mg/day) in exercise-induced asthma. One failed to show any benefit,110 whereas another showed that in some patients, it prevented airway constriction and reduced FEV1.111 

Vitamin E Vitamin E’s activity as an antioxidant, lipoxygenase inhibitor, and phospholipase inhibitor makes it a useful supportive agent in asthma treatment.112 

Selenium Reduced selenium levels have been demonstrated in asthma patients.113–115 Glutathione peroxidase, a selenium-dependent metalloenzyme, is important for reducing hydroperoxyeicosatetraenoic acid (HPETE) to HETE acid, thereby reducing leukotriene formation. Reduced levels of glutathione peroxidase have also been reported for patients with asthma.113 Supplemental selenium appears warranted to address any deficiency of glutathione peroxidase. In addition, supplemental selenium may reduce the production of leukotrienes by ensuring the optimal activity of glutathione peroxidase. 

Vitamin B12 Jonathan Wright, MD, believes that “B12 therapy is the mainstay in childhood asthma.”116 In one clinical trial, weekly intramuscular injections of 1000 mg produced definite improvements in patients with asthma.117 Of 20 patients, 18 showed less shortness of breath on exertion as well as improved appetite, sleep, and general condition. Vitamin B12 appears to be especially effective in sulfite-sensitive individuals. It offers the best protection when given orally (1–4 mcg) before challenge compared with other pharmacological agents (e.g., cromolyn sodium, atropine, doxepin).118 The mode of action is the formation of a sulfite– cobalamin complex that blocks sulfite’s effect. 

Magnesium In 1912 Trendelenburg demonstrated that magnesium relaxed bovine bronchial smooth muscle in vitro.119 Later, uncontrolled clinical studies revealed magnesium’s beneficial effect in the treatment of patients with acute attacks of bronchial asthma.120 Unfortunately, this promising line of research was dropped as antihistamines and bronchodilators became available. However, the advent of calcium channel blockers for the treatment of asthma generated renewed interest in the therapeutic use of magnesium for asthma. In fact, intravenous magnesium (2 g of magnesium sulfate infused every hour up to a total of 24.6 g) is now a well-proven and clinically accepted measure to halt an acute asthma attack as well as acute exacerbations of chronic obstructive pulmonary disease.121–125 Although these initial studies used injectable magnesium, it has been demonstrated that this is not necessary to restore magnesium status except in the case of an emergency situation such as an acute heart attack or an acute asthma attack.126 Oral magnesium therapy is an effective measure to raise body magnesium stores, but it will usually take 6 weeks to achieve significant elevations in tissue magnesium concentrations. Oral supplementation appears to be warranted because low levels of plasma magnesium have been found in asthmatic patients,92 and dietary magnesium intake is independently related to lung function and the severity of asthma.127 Several double-blind studies in adults and children with asthma have demonstrated improvements in respiratory function, antioxidant status (i.e., increased glutathione

CHAPTER 148  concentrations), reduced reactivity to chemical challenge to methacholine, and measures of asthma control and quality of life.128–130 The dosages used ranged from 300 mg a day in children to 340 mg a day in adults, usually in divided dosages. Isotonic nebulized magnesium has also proved useful as an adjunct treatment to standard bronchodilation therapies in patients with severe asthma, with a greater response in those with life-threatening asthma.131 A randomized controlled trial investigated the effect of inhaled magnesium sulfate on the treatment response in emergency department (ED) patients with moderate to severe asthma.132 Subjects allocated to the study group were treated with a standard protocol, plus 3 mL of 260 mmol/L solution of magnesium sulfate every 20 to 60 minutes. The control group was treated with nebulized saline as a placebo in addition to the standard protocol. The results demonstrate that adding nebulized magnesium sulfate to standard therapy in patients with moderate to severe asthma attacks led to greater and faster improvement in PEFR, respiratory rate, oxygen saturation, and respiratory rate and reduces hospitalization rates. 

Vitamin D Vitamin D deficiency is linked to increased airway reactivity, poorer lung function, and worse asthma control.133 One study in more than 1000 children with asthma showed that 35% were vitamin D–insufficient, as defined by a level of 30 ng/mL or less of 25-hydroxyvitamin D.134 After adjusting for age, sex, body mass index, income, and treatment group, insufficient vitamin D status was associated with higher odds of hospitalization or emergency department visits (OR 1.5). In addition to correcting a vitamin D insufficiency, vitamin D supplementation may improve asthma control by blocking the cascade of inflammation-causing proteins in the lung as well as increasing the production of interleukin-10, which has anti-inflammatory effects. Preliminary clinical evidence is encouraging, especially in the prevention of childhood asthma, at a dosage of 1200 IU per day of vitamin D3.135 Although there is conflicting evidence from clinical trials, results from in  vivo and in  vitro studies in animals and humans have suggested that supplementation with vitamin D may ameliorate several hallmark features of asthma, and vitamin D deficiency may influence the inflammatory response in the airways.136 

Botanical Medicines Asthma patients commonly employ self-treatment with botanicals. A cross-sectional analysis of 601 adults with asthma found that 14% used either herbal products, coffee, or black tea to treat their condition. Unfortunately, this study illustrated that those who used these methods had a higher incidence of hospitalizations.137 Because of the possibility of improper use of botanicals and the inability of the users to recognize the need for acute conventional interventions, it is recommended that before using natural therapies, patients with asthma consult a naturopathic physician or other qualified practitioner who understands the proper use of botanicals and can assess the asthmatic patient’s severity of risk. The most popular historical herbal treatment of asthma involved the use of Ephedra sinensis (Ma huang) in combination with herbal expectorants. This approach appeared to have considerable merit because Ephedra and its alkaloids have proven to be effective as bronchodilators in treating mild to moderate asthma and hay fever.138,139 Ephedra preparations containing ephedrine alkaloids are no longer sold in the United States because of safety concerns. However, ephedra extracts without ephedrine are still legally sold.

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Hedera helix (Ivy) In Europe, herbal preparations containing extracts from the leaves of ivy are popular for the relief of cough as well as asthma. In 2007 more than 80% of herbal expectorants prescribed in Germany comprised ivy extract and amounted to nearly 2 million prescriptions nationwide. Ivy leaf contains saponins that show expectorant, mucolytic, spasmolytic, bronchodilatory, and antibacterial effects. The mucolytic and expectorant actions of ivy are based on indirect beta2 adrenergic effects, and these actions are due to the saponins α-hederin and hederacoside C, the latter of which is metabolized to α-hederin when ingested.140 The indirect effect involves α-hederin, which inhibits the intracellular uptake of beta2 receptors and leads to an increased beta2-adrenergic response of the cell. A 2003 meta-analysis of three double-blind studies in children showed that the ivy preparations used were significantly superior to placebo.141 Among the three trials, one study compared ivy leaf extract cough drops to placebo, one compared suppositories to drops, and one tested syrup against drops. The reviewers concluded that ivy leaf extract preparations are effective with respect to the improvement of respiratory function in children with chronic bronchial asthma but noted that the study had a meager database to assess. In the only placebo-controlled double-blind study reviewed, 24 children with asthma between the ages of 4 and 12 were given a dry ivy leaf extract (35 mg) in cough drops or placebo for 3 days with a washout of 3 to 5 days before crossing over to the other treatment. The superiority of ivy leaf extract over placebo was noted by small improvements in airway resistance, residual volume, vital capacity, FVC, and FEV1 when the baseline measurements were compared with day 3 at 3 hours postdosing (morning dose). 

Glycyrrhiza glabra Licorice root has a long history of use as an anti-inflammatory and antiallergic agent, as documented in the scientific literature (see Chapter 85). The primary active component of licorice root in this application is glycyrrhetinic acid, a compound that has shown cortisol-like activity. In particular, glycyrrhetinic acid has been shown to inhibit phospholipase A2, the enzyme responsible for cleaving arachidonic acid from the phospholipid membrane pool and initiating eicosanoid synthesis.142 Licorice is also an expectorant, which is useful in the treatment of asthma. 

Lobelia inflata Indian tobacco contains the alkaloid lobeline, an efficient expectorant. Although it has a long history of use in asthma, it does promote bronchoconstriction and is a respiratory stimulant in vitro.143 This appears to suggest a cholinergic effect in the respiratory system; it also binds to nicotine acetylcholine receptors in the ganglions, thus promoting the release of epinephrine and norepinephrine. It is this action on adrenal hormone secretion that is responsible for lobelia’s therapeutic effects.144 Lobelia has traditionally been used in combination with other botanical agents, such as Capsicum frutescens and Symphlocarpus factida. 

Capsicum frutescens Experimental evidence has shown that capsaicin, cayenne pepper’s major active component, induces long-lasting desensitization of airway mucosa to various mechanical and chemical irritants.145 This effect is probably due to capsaicin-induced depletion of substance P (which normally increases vascular permeability and flow) in the respiratory tract nerves. Substance P is an undecapeptide associated with “neurogenic inflammation” via a direct effect and a synergistic action with histamine on the peripheral nervous system.146 The respiratory

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and gastrointestinal tracts have large numbers of substance P–containing neurons. Because of its location and physiological action, it is believed to play an important role in atopic conditions such as asthma and atopic dermatitis. Therefore depletion of substance P may be beneficial in these conditions. 

Zizyphi fructus The jujube plum has been used extensively in Chinese medicine for the treatment of asthma and allergic rhinitis.147 It contains 100 to 500 nmol/g of cyclic-AMP (cAMP) per dry weight, a concentration 10 times greater than that of any other plant or animal tissue thus far reported in the literature.148 It also contains a beta-adrenergic receptor stimulator that raises cAMP levels. These experimental findings, in conjunction with Zizyphi’s long historical use, strongly support its clinical use. 

Thea sinensis Green tea is useful as an adjunctive in asthma treatment due to its methylxanthine and antioxidant components (see Chapter 60). 

Allium Family Onions and garlic inhibit lipoxygenase and cyclooxygenases, which generate TxA2, PGD2, and PGE2 .149 Oral pretreatment of guinea pigs (that were sensitized to ovalbumin) with 1 mL of an alcohol/onion extract markedly reduced the asthmatic response to allergen inhalation challenges. Onion contains quercetin, which may account for some of its pharmacological effect,150 but the major protective actions appear to be related to its content of benzyl and other isothiocyanates (mustard oils).151 Although the mechanism of action is unknown, it has been suggested that it is due to the inhibition of the biosynthesis of arachidonic acid metabolites. 

Tylophora asthmatica The leaves of Tylophora asthmatica have been used extensively in Ayurvedic medicine in asthma and other respiratory tract disorders. The mode of action of Tylophora is unknown but is thought to be due to the alkaloids, especially tylophorine, which have been reported to possess antihistamine and antispasmodic activity, as well as inhibition of mast-cell degranulation.152,153 However, a more central mechanism may be responsible for the clinical effects in asthma. Several double-blind clinical studies have shown Tylophora to be beneficial for asthma.154–157 In one study of 135 patients, those given 200 mg of Tylophora leaves twice daily for 6 days demonstrated improvements in symptoms and respiratory function during the treatment period and for up to 2 weeks after treatment.154 In another double-blind study of 103 patients, those receiving 40 mg of the dry alcoholic extract of Tylophora indica daily for only 6 days demonstrated significant improvement in symptoms of asthma compared with a placebo group.156 At the end of the first week, 56% had complete to moderate improvement, compared with 31.6% of the 92 patients receiving the placebo. At the end of 4 weeks, the respective figures were 32% and 23.8%; at 8 weeks, 23.8% and 8.4%; and at 12 weeks, 14.8% and 7.2%. The incidence of side effects such as nausea, partial diminution of taste for salt, and slight mouth soreness was 16.3% in the Tylophora group and 6.6% in the placebo group. These results, as well as the results from an additional study, indicate that the benefits of Tylophora are short-lived.157,158 

Ginkgo biloba G. biloba contains several unique terpene molecules known collectively as ginkgolides that antagonize platelet-activating factor (PAF), a key chemical mediator in asthma, inflammation, and allergies. Ginkgolides compete with PAF for binding sites and inhibit the various events

induced by PAF. The antiasthmatic effects of orally administered or inhaled ginkgolides have been shown to produce improvements in respiratory function and to reduce bronchial reactivity in several double-blind studies.158,159 Treatment consisted of 120 mg of the pure ginkgolides daily—a dosage that is currently expensive to achieve using the 24% ginkgo flavonglycoside and 6% total terpenoid G. biloba extract. 

Aloe vera In one study, the oral administration of an extract of Aloe vera for 6 months was shown to produce good results in the treatment of asthma in some individuals of various ages.160 The extract was produced from the supernatant of fresh leaves stored in the dark at 4°C for 7 days. Subjecting the leaves to dark and cold results in an increase in the polysaccharide fraction. One gram of the crude extract obtained from leaves stored in a cold, dark environment produced 400 mg of neutral polysaccharide, compared with only 30 mg produced from leaves not subjected to cold or dark. The dosage was 5 mL of a 20% solution of the A. vera extract in saline twice daily for 24 weeks, and 11 of 27 patients (40%) without corticosteroid dependence felt better at the study’s conclusion. The mechanism of action is thought to be via restoration of protective mechanisms, followed by augmentation of the immune system. 

Coleus forskohlii Coleus forskohlii extracts may be particularly useful in asthma because increasing intracellular levels of cAMP result in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in patients with asthma (see Chapter 69).161,162 These studies used inhaled doses of pure forskolin. Whether orally administered forskolin in the form of C. forskohlii extract would produce similar bronchodilatory effects has yet to be determined. However, on the basis of the plant’s historic use and additional mechanisms of action, it appears likely. 

Boswellia The Indian Ayurvedic botanical Boswellia is known for its ability to inhibit leukotriene biosynthesis.163 In one double-blind, placebo-controlled study, bronchial asthma was reduced in 70% of 40 patients treated with gum resin at 300 mg three times daily for 6 weeks, whereas only 27% of the control group improved. The disappearance of physical symptoms and signs such as dyspnea and rhonchi; fewer attacks; increased FEV1, vital capacity, and peak expiratory flow rate (PEFRs); and decreased eosinophilia counts and sedimentation rates were recorded as measures of improvement.163 

Acupuncture and Acupressure In traditional Chinese medicine, chronic asthmatic symptomatology is usually characterized as a lung or spleen deficiency. This model considers that acute symptoms may be caused by environmental invasion from cold wind (environmental factors) or an internal condition stemming from a lung heat condition (increased inflammation and eosinophilia). Chronic asthma is considered more of a weakness in the lung itself or a weakness of the spleen, which is responsible for nourishing the lung qi (or vitality). In traditional Chinese medicine, the emotion of grief is also said to weaken lung qi. In one prospective randomized study of patients with chronic asthma, 41 patients with chronic obstructive asthma were randomly assigned to receive acupuncture in addition to standard care, acupressure and standard care, or standard care alone. For each subject, 20 acupuncture treatments were given, and self-administered acupressure was performed daily for 8 weeks. On the St. George’s Respiratory

CHAPTER 148  Questionnaire, the acupuncture subjects showed an average 18.5-fold improvement, whereas the improvement for the acupressure-only subjects was 6.57-fold. Additionally, for patients who received acupressure, the irritability domain score exhibited an 11.8-fold improvement.164 Another study involved 44 patients receiving bona fide or sham acupressure. They received five treatments per week lasting 16 minutes each for 4 weeks. Using pulmonary function and dyspnea scores, 6-minute walking distance measurements, and State Anxiety Scale scores, the acupressure group had significant improvements in breathing and less anxiety compared with those of the sham group.165 

THERAPEUTIC APPROACH The effective treatment of asthma requires the consideration and control of many aspects. In particular, the specific underlying defects and initiating factors must be determined because many different defects and metabolic abnormalities result in the same clinical picture of asthma. The development of an appropriate treatment plan includes the following five steps: 1. Determining and rectifying the underlying defect that allows the development of sensitization 2. Determining and balancing the underlying metabolic defect that causes an excessive inflammatory response 3. Finding potential allergens and developing a lifestyle, diet, and environment that allow the allergens to be avoided 4. Modulating the inflammatory process to limit the severity of the response 5. Preparing an effective treatment for the bronchoconstriction of the acute attack

Environment The most important preventative measures are to decrease exposure through decreased pollution in the work and home environments, the use of airway protection during the most-exposed work tasks, and cessation of smoking. Airborne allergens such as pollen, dander, and dust mites166 are often difficult to avoid entirely, but measures can be taken to reduce exposure. Eliminating dogs, cats, carpets, rugs, upholstered furniture, and other surfaces where allergens can collect is a great first step. Also, methods to discourage the presence of dust mite and cockroach antigen should be used, although pesticide exposure should be minimized. If environmental exposures cannot be controlled entirely, make sure that the bedroom is as allergy-proof as possible. Have the patient encase the mattress in an allergen-proof plastic; wash sheets, blankets, pillowcases, and mattress pads every week; consider using bedding material made from Ventflex, a special hypoallergenic synthetic material; and install an air purifier. The best mechanical air purifiers are high-efficiency particulate-arresting filters that can be attached to central heating and air-conditioning systems. These units are available from suppliers of heating and air-conditioning units. Environmental chemicals around the home should be removed. These include paints, solvents, new furniture, chemical cleaners, and scented candles/air fresheners, to name a few. Building materials containing formaldehyde (e.g., carpeting, cabinetry) should also be avoided. Perfume, cologne, hair spray, lotions, antiperspirant, and scented soaps and shampoos often contain several chemicals that should be avoided. Water-damaged buildings must be repaired, and all mold, bacterial, and other organism growth must be addressed by professionals experienced in mold remediation. 

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Diet Organic, mostly plant-based foods should be consumed when possible. Any foods known to cause adverse reactions should also be avoided. Elimination of the offending foods and incorporation of an oligoantigenic diet are primary in reducing inflammation. Elimination diets have been successful in identifying allergens and treating asthma, especially in infants. The patient who has many food allergies may have to use a 4-day rotation diet. In the early stages of treatment, mild dietary tryptophan reduction should be useful but is not critical unless there is a metabolic defect in tryptophan metabolism. Garlic and onions should be used liberally unless the patient reacts to them. If the patient is willing or his or her asthma is unresponsive to this recommended therapy, a vegan diet should be tried (for a minimum of 4 months), with the possible exception of coldwater fish. Moderate fruit consumption, especially of apples, should also be encouraged. 

Supplements • V  itamin B6: 25 to 50 mg two times a day • Vitamin B12: 1000 mcg/day (oral) or weekly injection; evaluate for efficacy after 6 weeks • Vitamin C: 10 to 30 mg/kg in divided dosages • Vitamin D: 1000 to 8000 IU daily. Monitor blood levels to determine needed dosage because there is wide variability. Those whose blood levels do not rise in response to supplementation should have their 1,25(OH)2D3 checked. Also, Vitamin K2 should always be prescribed with Vitamin D. • Vitamin E: 100 to 200 IU daily • Magnesium: 200 to 400 mg three times a day • Quercetin: 400 mg 20 minutes before meals or enzymatically modified isoquercitrin (EMIQ) 100 mg daily. • Grape seed extract (95% PCO content) or pine bark extract (e.g., Pycnogenol): 150 to 300 mg daily • Lycopene: 30 to 45 mg/day • Selenium: 200 mcg/day 

Botanical Medicines Choose one or more of the following botanical medicines.

Hedera helix Ivy leaf is available primarily in tincture and fluid extract, and the dry-powdered extract comes in the form of capsules and tablets. Based on clinical studies, the daily dosages should deliver the following equivalent to dried herbal substance: 1 to 5 years: 150 mg; 6 to 12 years: 210 mg; over 12 years: 420 mg. The typical dosage of a 4:1 powdered extract for adults and children over 12 years of age is 100 mg daily. 

Lobelia inflata • D  ried herb: 0.2 to 0.6 g three times a day • Tincture: 15 to 30 drops three times a day • Fluid extract: 8 to 10 drops three times a day 

Glycyrrhiza glabra • P  owdered root: 1 to 2 g • Fluid extract (1:1): 2 to 4 mL (½–1 Tsp) • Solid (dry-powdered) extract (4:1): 250 to 500 mg 

Camellia sinensis Liberal use (green tea only)

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Tylophora asthmatica 200 mg of Tylophora leaves or 40 mg of the dry alcoholic extract two times daily

Coleus forskolii Extract standardized to contain 18% forskolin: 50 mg (9 mg of forskolin) two to three times daily 

Counseling For patients who respond to emotional crises with asthmatic attacks, counseling is important. Counseling is also important for children with moderate to severe asthma, who may develop behavioral problems. 

Acupuncture and Acupressure Regular acupuncture and home acupressure treatments should be used. 

IN ACUTE ATTACK An acute asthma attack can be a medical emergency. If necessary, the patient should be referred to an emergency department immediately.

There are two more natural approaches that can be considered, but research support is only anecdotal. Intravenous (IV) magnesium can quickly relieve bronchial spasm. This should only be done by those with proper training and facilities. Dr. Bastyr recommended an herbal protocol using 1 tsp every 15 minutes of a tincture containing equal parts capsicum, lobelia, and skunk cabbage, which the senior editor found consistently effective. Before prescribing, practitioners are advised to try this intense intervention themselves first. If the patient does not immediately respond to either of these two interventions, then emergency intervention is required.

REFERENCES See www.expertconsult.com for a complete list of references.

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158. Wilkens JH, Wilkens H, Uffmann J, et al. Effects of a PAF-antagonist (BN 52063) on bronchoconstriction and platelet activation during exercise induced asthma. Br J Clin Pharmacol. 1990;29:85–91. 159. Guinot P, Brambilla C, Duchier J, et al. Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients. A preliminary study. Prostaglandins. 1987;34:723– 731. 160. Shida T, Tagi A, Nishimura H, et al. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med. 1985;51:273–275. 161. Lichey J, Friedrich T, Priesnitz M, et al. Effect of forskolin on methacholine-induced bronchoconstriction in extrinsic asthmatics. Lancet. 1984;2:167. 162. Bauer K, Dietersdorfer F, Sertl K, et al. Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther. 1993;53:76–83. 163. Wildfeuer A, Neu IS, Safayhi H, et al. Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis. Arzneimittelforschung. 1998;48:668–674. 164. Maa SH, Sun MF, Hsu KH, et al. Effect of acupuncture or acupressure on quality of life of patients with chronic obstructive asthma: a pilot study. J Altern Complement Med. 2003;9:659–670. 165. Wu HS, Wu SC, Lin JG, et al. Effectiveness of acupressure in improving dyspnoea in chronic obstructive pulmonary disease. J Adv Nurs. 2004;45:252–259. 166. Van Woerden H. Dust mites living in human lungs—the cause of asthma? Med Hypotheses. 2004;63:193–197.

149 Atherosclerosis John Nowicki, ND, and Michael T. Murray*, ND

OUTLINE Diagnostic Summary, 1131 General Considerations, 1131 Understanding Atherosclerosis, 1131 Causative Factors, 1132 Determining a Patient’s Risk, 1132 Clinical Evaluation, 1132 Risk Factors, 1132 Therapeutic Considerations—General Guidelines, 1136 Diet—General Guidelines, 1136 Therapeutic Considerations—Lowering Cholesterol, 1139 The Importance of Soluble Dietary Fiber in Lowering Cholesterol, 1139 Natural Products to Lower Cholesterol Levels, 1140 Comparing Natural Cholesterol-Lowering Agents, 1142 Therapeutic Considerations—Antioxidant Status, 1143 Vitamin E, 1143 Vitamin C, 1144 Grape Seed and Pine Bark Extracts, 1144

Therapeutic Considerations—Miscellaneous Risk Factors, 1144 Platelet Aggregation, 1144 Fibrinogen, 1145 Homocysteine, 1145 “Type A” Personality, 1145 Other Nutritional Factors, 1146 Therapeutic Considerations—Preventing a Recurrent Heart Attack, 1147 Aspirin, 1147 Dietary Alternatives to Aspirin, 1147 Preventing a Subsequent Stroke, 1147 Other Considerations, 1147 Therapeutic Approach, 1148 Dietary Recommendations, 1148 Lifestyle Recommendations, 1148 Supplements, 1148

DIAGNOSTIC SUMMARY

treatment of CVD, it is necessary to examine closely the structure of an artery and the process of atherosclerosis.

• C  haracteristically associated with high blood pressure, weak pulse, and wide pulse pressure • Symptoms and signs depend on the arteries involved and degree of obstruction: angina, leg cramps (intermittent claudication), gradual mental deterioration, weakness, or dizziness • May also occur without symptoms • Diagonal earlobe crease 

GENERAL CONSIDERATIONS Atherosclerosis refers to the process that is the underlying pathology in a group of clinical entities collectively referred to as cardiovascular disease (CVD) including: heart disease (atherosclerosis of the coronary arteries); coronary artery disease (CAD); and myocardial, pulmonary, and cerebral infarction. Despite a steady decline in the age-adjusted death toll since 1980, CVD remains the number-one cause of death in the United States, where it is responsible for 1 of every 2.8 deaths. In 2015 nearly 634,000 deaths were attributed to heart disease and nearly 140,000 deaths to stroke in the United States.

Understanding Atherosclerosis To fully understand the important ways in which various natural measures described in this chapter affect the health of the arteries and * Previous edition contributor

Structure of an Artery An artery is divided into three major layers: • The intima, representing the endothelium or internal lining of the artery, consists of a layer of endothelial cells lined by glycosaminoglycans (GAGs) to protect them from damage as well as to promote repair. Beneath the surface cells is the internal elastic membrane, composed of a layer of GAGs and other ground substance compounds, which supports the endothelial cells and separates the intima from the smooth muscle layer. • The media consists primarily of smooth muscle cells. Interposed among the cells are GAGs and other ground substance structures that provide support and elasticity to the artery. • The adventitia, or external elastic membrane, consists primarily of connective tissue, including GAGs; it provides structural support and elasticity to the artery. 

The Process of Atherosclerosis The lesions of atherosclerosis are initiated in response to injury to or a disruption of the normal functioning of the arterial endothelium.1 The progression of atherosclerosis is detailed as follows: 1. The initial step is damage or dysfunction of the vascular endothelium. Damage results from weakening of the GAG layer, which protects the endothelial cells, due to the same factors that damage the endothelial cells (e.g., insulin resistance, reactive oxygen and

1131

1132

SECTION 6 

Environmental factors

Diseases Genetic factors

Conventional risk factors (Diabetes, dyslipidemia, hypertension, obesity, etc.)

Subclinical atherosclerosis (FMD↑, PWV↑, carotid IMT↑, etc.)

Clinical atherosclerotic disease (CAD, stroke, PAD, etc.)

BOX 149.1  Major Risk Factors for

Atherosclerosis

• Smoking • Elevated blood cholesterol levels • High blood pressure • Diabetes • Physical inactivity • Other risk factors

TABLE 149.1  Association of Risk Factors

With the Incidence of Atherosclerosis

Fig. 149.1  Atherosclerosis is a multifactorial disease, and the development of atherosclerotic disease involves the interaction of many genetic and environmental factors, as well as conventional risk factors, such as diabetes, dyslipidemia, hypertension and obesity. CAD, coronary artery disease; FMD, flow-mediated vasodilation; IMT, intima-media thickness; PAD, peripheral artery disease; PWV, pulse wave velocity. (From Katakami N, Kaneto H, Shimomura I. Carotid ultrasonography: a potent tool for better clinical practice in diagnosis of atherosclerosis in diabetic patients. J Diabetes Investig. 2014;5[1]:3-13.)

Major Risk Factors

Increase In Incidence

Presence of one of the major risk factors High cholesterol and high blood pressure High cholesterol and a smoker High blood pressure and a smoker Smoker, high blood cholesterol, and high blood pressure

30% 300% 350% 350% 720%

nitrogen species, impaired repair processes, metal toxicity, hyperhomocysteinemia, and inhibition of either nitric oxide production or availability). 2. Once the endothelial cells have been sufficiently damaged, sites of injury become more permeable to plasma constituents, especially lipoproteins. The binding of lipoproteins to GAGs leads to a breakdown in the integrity of the ground substance matrix and causes an increased affinity for cholesterol. Simultaneously, monocytes, T lymphocytes, and platelets adhere to the damaged area, where they release growth factors that stimulate smooth muscle cells to migrate from the media into the intima and replicate. 3. Local concentration of lipoproteins, monocytes, and platelets leads to the migration of smooth muscle cells from the media into the intima, where they undergo proliferation. Smooth muscle cells dump cellular debris into the intima, leading to the further development of plaque. 4. Formation of a fibrous cap (consisting of collagen, elastin, and GAGs) over the intimal surface occurs. Fat and cholesterol deposits accumulate. 5. Plaque continues to grow until eventually it either blocks the artery directly or ruptures to form a clot that travels the general circulation until it occludes a blood vessel. Plaque instability is associated with a significantly greater risk for myocardial infarction (MI) or stroke.1 Thus targeting plaque stabilization appears to be more clinically important than simply enlarging the lumen. 

BOX 149.2  Other Risk Factors for

Causative Factors Prevention of CVD involves reducing and, when possible, eliminating various risk factors (Fig. 149.1). Risk factors are divided into two primary categories: major risk factors and other risk factors. Box 149.1 lists the major risk factors. Risk for a heart attack increases with the number of major risk factors (Table 149.1). In addition to these well-accepted major risk factors, numerous others have occasionally been shown to be more significant (Box 149.2). It is also important to develop a strategic approach to plaque stabilization by addressing endothelial dysfunction, increased local and systemic inflammation, increased reactive oxygen species, the activation of mast cells, and the infiltration and activation of macrophages. 

Atherosclerosis

• Insulin resistance • Low thyroid function (see Chapter 182) • Low antioxidant status • Elevations of C-reactive protein • Low levels of essential fatty acids • Increased platelet aggregation • Increased fibrinogen formation • Low levels of magnesium and potassium • Elevated levels of homocysteine • “Type A” personality

Determining a Patient’s Risk To help determine a patient’s overall risk for having a heart attack or stroke, the following risk-determinant scale may prove useful. Although this risk assessment does not take into consideration several other important factors—such as the level of C-reactive protein, lipoprotein(a)[Lp(a)], fibrinogen, and coping style—the score provides a good indication of a patient’s risk for a heart attack or stroke (Table 149.2). 

Clinical Evaluation Clinical cardiovascular assessment may include various laboratory and imaging such as the tests listed in Box 149.3. 

Risk Factors Smoking

Statistical evidence reveals smokers have a 70% greater risk of death from CVD than nonsmokers.2 The more cigarettes smoked and the longer the period of years a person has smoked, the greater the risk of dying from a heart attack or stroke. Overall, the average smoker dies 7 to 8 years sooner than the nonsmoker. Tobacco smoke contains more than 4000 chemicals, of which more than 50 have been identified as carcinogens. These chemicals are extremely damaging to the cardiovascular system. Many of these

CHAPTER 149 

TABLE 149.2  Risk-Determination Scale for

Heart Disease and Stroke

SCALE OF RISK Blood pressure (systolic) Blood pressure ­(diastolic) Smoking (cigarettes per day) Heredity Ia Heredity IIb Diabetes duration (years) Total cholesterol (mg/dL) HDL-C (mg/dL) Total cholesterol/ HDL-C ratioc Exercise (hours per week) Supplemental EPA/ DHA (mg) intake Supplemental vitamin C (mg) and vitamin E (IU) intake Average daily servings of fruits and vegetables Age Subtotals

1

2

3

4

5

5) increased the risk for a CHD event by approximately sixfold. A large meta-analysis of 17 prospective trials reported that an 88 mg/dL (1.0 mmol/L) increase in plasma triglyceride levels significantly increased the relative risk of CVD by approximately 30% in men and 75% in women. The corresponding rates were somewhat lower (14% and 37%, respectively) but still statistically significant after adjustment for HDL-C level.15 This increased risk is mediated through the metabolic interrelationships between serum triglyceride (TG) levels and other risk factors, such as the atherogenic lipid profile (low HDL-C levels and elevated small dense LDL levels), insulin resistance, a prothrombotic propensity, and low-grade systemic inflammation. TG-lowering strategy in patients with HTG is an important clinical goal in reducing the risk of not only atherosclerosis but also the metabolic syndrome and diabetes.  Inherited elevations of cholesterol and triglycerides.  Elevations of blood cholesterol, triglycerides, or both can be due to genetic factors. These conditions are referred to as familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH), and familial hypertriglyceridemia (FHTG). Relatively speaking, these disorders are among the most common inherited diseases, affecting about 1 in every 500 people. The problem in FH is a defect in the receptor protein for LDL-C in the liver. Normally, the LDL-C receptor is responsible for removing cholesterol from the blood. When the liver cell takes up the LDL-C after it has bound to the receptor, it signals the liver cell to stop making cholesterol. In FH, the defect in the LDL-C receptor results in the liver not receiving the message to stop making cholesterol. Damage to the LDL-C receptor occurs with normal aging and in several disease states. Diabetes may be the most significant disease owing to increased glycosylation of the receptor proteins. As a result of damage to the LDL-C receptor, cholesterol levels tend to rise with age. In addition, a diet high in saturated fat and cholesterol decreases the number of LDL-C receptors, thereby reducing the feedback mechanism that tells the liver cell to decrease cholesterol synthesis. Lifestyle and dietary changes can increase the function or number of LDL-C receptors or both. The most dramatic effects are in people without inherited causes of elevated cholesterol or triglycerides or both, but even people with FH can benefit. FCH and FHTG result in defects that are similar to those of FH. In FCH, the basic defect appears to be an accelerated production of VLDL

CHAPTER 149  in the liver. These individuals may have only a high blood triglyceride level, only a high cholesterol level, or both. In FHTG, there is only an elevation in blood triglyceride levels, and HDL-C levels tend to be low. The defect in FHTG is that VLDL particles made by the liver are larger than normal and carry more triglycerides. FHTG is aggravated by diabetes, gout, and obesity. 

Diabetes Atherosclerosis is one of the key underlying factors in the development of many chronic complications of diabetes. Individuals with diabetes have a twofold to threefold higher risk of dying prematurely of heart disease or stroke than persons who do not have diabetes, and 55% of deaths in patients with diabetes are caused by CVD. However, even mild insulin resistance and poor glucose control have both been shown to have a dramatic effect on the incidence and progression of CVD. For more information, see Chapter 165. 

Elevated Blood Pressure Elevated blood pressure is often a sign of considerable atherosclerosis and a major risk factor for heart attack or stroke. In fact, the presence of hypertension is generally regarded as the most significant risk factor for stroke. For more information, see Chapter 179. 

Physical Inactivity Physical activity refers to “bodily movement produced by skeletal muscles that requires energy expenditure” and produces healthy benefits. Exercise, a type of physical activity, is defined as “a planned, structured, and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” Physical inactivity denotes a level of activity less than that needed to maintain good health. Physical inactivity characterizes most Americans, because roughly 54% of adults report little or no regular leisure physical activity, and there is also a sharp decline in regular exercise among children and adolescents.1 Physical activity protects against the development of CVD and favorably modifies other CVD risk factors, including high blood pressure, blood lipid levels, insulin resistance, and obesity. Physical activity is also important in the treatment and management of patients with CVD or increased risk including those who have hypertension, stable angina, a prior MI, peripheral vascular disease, heart failure, or who are recovering from a cardiovascular event. 

Environmental Toxins Particulate matter.  Cumulative epidemiological and experimental data have shown that exposure to air pollutants leads to increased cardiovascular ischemic events and enhanced atherosclerosis. In approximately 43 million adults from the APHEA2 (Air Pollution and Health: A European Approach) study, it was found that daily cardiovascular mortality increased 1.5% for every 20 μg/m3 increase in PM10.16 Ultrafine particles (1 for men and >0.8 for women) • Atherogenic dyslipidemia (mainly triglycerides >150 mg/dL and low HDL-C [90%) and HLA-DQ8 (5%–10%).4 Only 3% of individuals with one or both of these alleles develop CD, yet up to 40% of the general population has one of them. Therefore their presence is not diagnostic of CD, but their absence excludes a diagnosis of CD. Genetic testing is available for the assessment of CD. Findings of inflammatory changes in jejunal biopsies, ranging from lymphocytic enteritis to various

Fig. 164.1  Dermatitis Herpetiformis.

1259

1260

Diseases

SECTION 6 

GUT

Gluten

SKIN

LUMEN EPITHELIUM

Gliadin Amide hydrolysis

EPIDERMIS N NN N N N NNN N NN N N N

eTG

LAMINA PROPRIA

tTG Cross-reactivity

cDC

M1

LN or PP

HL

M1

PRR?

AD

Q2

TH

&D

B

Q8

PRR?

IL-8

Neutrophil Recruitment N N N

DERMIS

IL-8 Neutrophil Recruitment

N NN

Fig. 164.2  Cross-reactivity Hypothesis of Dermatitis Herpetiformis in Celiac Disease.

lesions found in patients with DH are extremely itchy grouped vesicles most frequently located on extensor surfaces. Intense pruritus is the predominant symptom; however, DH is a clinical chameleon and can present with excoriations, eczematous lesions, or minimal patterns of discrete erythema or digital purpura.9 

PATHOGENESIS OF DH: FROM GUT TO SKIN At the present time, the immunopathogenesis of DH is believed to originate from occult CD in the gut with a tissue transglutaminase (TG2) autoantigen response, and possibly also an IgA epidermal transglutaminase (TG3) autoantibody response (Fig. 164.2). This results in an immune complex deposition of high-avidity IgA TG3 antibodies to the TG3 enzyme in the papillary dermis. This mechanism is supported by GFD results. TG3 and TG2 antibodies in serum disappear with the diet, the small intestine heals, and eventually the rash clears. However, the IgA–TG3 complexes in the dermis disappear quite slowly with the GFD, presumably because the active TG3 enzyme in the complexes results in cross-linkage of the complex to the dermal structures.10 

THERAPEUTIC CONSIDERATIONS Gluten The most important factor in the treatment of patients with DH is the elimination of all sources of gluten. Frazer’s criteria for the diagnosis of gluten-sensitive enteropathy (improvement on a GFD and relapse after reintroduction) have been used in many studies and have shown conclusively that the rash and villous atrophy of DH are largely gluten dependent.11–16 Gluten elimination results in an improvement in virtually all patients, including the elimination of the reticulin and gluten antibodies found in patients with DH.3,17 Further study of the wheat connection has shown that the gliadin polypeptide of gluten is most likely the key antigen. Indirect immunofluorescence shows antibodies to gliadin in the sera of 45% of patients with DH. The titer and correlation increase with increasing severity of the disease; 81% of patients with severe jejunal abnormalities show antibodies to gliadin.18 Despite the published benefits of a GFD in the treatment of DH for more than 30 years, this treatment is still often omitted from

conventional dermatology and medical textbooks. The advantage of a GFD over drugs like dapsone (the most widely prescribed drug for DH) is obvious because this drug is often associated with severe side effects. In contrast, with a GFD: • Most patients (more than 65%) experience complete resolution, and the rest improve substantially. • There is complete resolution of the enteropathy associated with DH. • Harsh medications can be eliminated or substantially reduced. • Most patients experience an improved sense of well-being. Also of importance is that individuals who used a GFD rather than drugs are protected against developing non-Hodgkin’s lymphoma (NHL)19 because the risk of NHL is significantly increased in DH and CD.

Food Allergy Although gluten control is critical in the treatment of patients with DH, some (about 35%) are not adequately helped. In particular, only 50% of patients totally eliminate the cutaneous IgA deposits and develop normal jejunal tissue. This is probably because of the presence of other food allergies that, although not initiating, developed as a result of the increased leakage of macromolecules across the damaged intestinal mucosa. Milk has been found to be significantly problematic in some patients.20,21 Using a sensitive enzymelinked immunoassay (ELISA), 75% of DH patients were shown to have serum antibodies reactive against gliadin, bovine milk, or ovalbumin.22 These results suggest that other food sensitivities are implicated in DH. An elemental diet followed by careful food reintroduction usually produces better results than a simple gluten-free diet.23 

Para-Aminobenzoic Acid Para-aminobenzoic acid (PABA) has been used successfully in the control of DH, even in those patients who are not controlling the gluten content of their diet.24 However, because its use is recommended only for symptom control and it probably does not result in repair of the villous atrophy, it is not recommended as the treatment of choice but rather as an adjunct in unresponsive cases or to assist in particularly severe cases. 

CHAPTER 164 

Treatment of Nutritional Deficiencies Evaluations for deficiencies of iron, zinc, calcium, fat-soluble vitamins, and folic acid should be conducted; also, the possibility of homocysteinemia, osteopenia, and osteoporosis should be assessed and treated if found. 

THERAPEUTIC APPROACH After all sources of gluten and gliadin have been eliminated (see Appendix 6 for the gluten content of foods), a careful search should be made for other food allergies (for more detail, see Chapter 14). Once allergens have been identified and avoided, a therapeutic regimen similar to that for atopic dermatitis (see Chapter 150) should be used. Patience is necessary because a response may take several weeks to 6 months to be seen.

Dermatitis Herpetiformis

1261

Diet Use a healthy, whole-foods diet free of processed foods, gluten-containing grains, and foods found to be allergenic. 

Supplement PABA: 5 g/day until remission (maximum of 3 months)

REFERENCES See www.expertconsult.com for a complete list of references.

REFERENCES 1. Reunala T, Salmi TT, Hervonen K, et al. Dermatitis herpetiformis: a common extraintestinal manifestation of coeliac disease. Nutrients. 2018;10(5):602. 2. Rose C, Armbruster FP, Ruppert J, et al. Autoantibodies against epidermal transglutaminase are a sensitive diagnostic marker in patients with dermatitis herpetiformis on a normal or gluten-free diet. J Am Acad Dermatol. 2009;61(1):39–43. 3. Fry L, Leonard JN, Swain F, et al. Long term follow-up of dermatitis herpetiformis with and without dietary wheat gluten withdrawal. Br J Derm. 1982;107:631–640. 4. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391:70– 81. 5. Collin P, Vilppula A, Luostarinen L, et al. Review article: Coeliac disease in later life must not be missed. Aliment Pharmacol Ther. 2018;47:563–572. 6. Rodrigo L. Celiac disease. World J Gastroenterol. 2006;12:6585–6593. 7. Rodrigo L, Beteta-Gorriti V, Alvarez N, et al. Cutaneous and mucosal manifestations associated with celiac disease. Nutrients. 2018;10(7):800. https://doi.org/10.3390/nu10070800. 8. Ko CJ, Colegio OR, Moss JE, et al. Fibrillar IgA deposition in dermatitis-herpetiformis: an underreported pattern with potential clinical significance. J Cutan Pathol. 2010;37(4):475–477. 9. Pfeiffer C. Dermatitis herpetiformis: a clinical chameleon. Hautarzt. 2006;57(11):1021–1028. 10. Hietikko M, Hervonen K, Salmi T, et al. Disappearance of epidermal transglutaminase and IgA deposits from the papillary dermis of dermatitis herpetiformis patients after a long-term gluten-free diet. Br J Dermatol. 2018;178:e198–e201. https://doi.org/10.1111/bjd.15995. 11. Leonard J, Haffenden G, Tucker W, et al. Gluten challenge in dermatitis herpetiformis. N Engl J Med. 1983;308:816–819. 12. Savilahti E, Reunala T. Is dermatitis herpetiformis a gluten-sensitive enteropathy? Int J Dermatol. 1990;10:706–708.

13. Reunala T. Dermatitis herpetiformis: coeliac disease of the skin. Ann Med. 1998;30:416–418. 14. Kumar V, Zane H, Kaul N. Serologic markers of gluten-sensitive enteropathy in bullous diseases. Arch Derm. 1992;128:1474–1478. 15. Frodin T, Gotthard R, Hed J, et al. Gluten-free diet for dermatitis herpetiformis: the long term effect on cutaneous, immunological and jejunal manifestations. Acta Derm Venereol (Stockholm). 1981;61:405–411. 16. Garioch JJ, Lewis HM, Sargent SA, et al. 25 years’ experience of a gluten-free diet in the treatment of dermatitis herpetiformis. Br J Dermatol. 1994;131:541–545. 17. Fry L. Dermatitis herpetiformis: problems, progress and prospects. Eur J Dermatol. 2002;12:523–531. 18. Volta U, Cassani F, DeFranchis R, et al. Antibodies to gliadin in adult coeliac disease and dermatitis herpetiformis. Digestion. 1984;30:263–270. 19. Lewis HM, Renaula TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Derm. 1996;135:363–367. 20. Engquist A, Pock-Steen OC. Dermatitis herpetiformis and milk-free diet. Lancet. 1971;2:438–439. 21. Pock-Steen OC, Niordson AM. Milk sensitivity in dermatitis herpetiformis. Br J Derm. 1970;83:614–619. 22. Barnes RM, Lewis-Jones MS. Isotype distribution and serial levels of antibodies reactive with dietary protein antigens in dermatitis herpetiformis. J Clin Lab Immunol. 1989;30:87–91. 23. Kadunce DP, McMurry MP, Avots-Avotins A, et al. The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis. J Invest Dermatol. 1991;97:175–182. 24. Zarafonetis CJ, Johnwick EB, Kirkman LW, et al. Paraaminobenzoic acid in dermatitis herpetiformis. Arch Dermatol Syph. 1951;63:115–132.

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165 Diabetes Mellitus Types I and II Michael T. Murray, ND

OUTLINE Diagnostic Summary, 1262 General Considerations, 1262 Prediabetes and Metabolic Syndrome, 1263 Diagnostic Considerations, 1263 Glycosylated Hemoglobin, 1264 Risk Factors for Type 1 Diabetes, 1264 Environmental and Dietary Risk Factors, 1264 Early Treatment and Possible Reversal of Type 1 Diabetes, 1266 Niacinamide, 1266 Epicatechin, 1266 Risk Factors in Type 2 Diabetes, 1266 Genetics of Type 2 Diabetes and Obesity, 1267 Diet, Exercise, Lifestyle, and Diabetes Risk, 1267 Environmental Toxins, 1269 Lifestyle Management Versus Drugs to Prevent Type 2 Diabetes, 1270 Clinical Monitoring of Diabetes, 1270 Urinary Glucose Monitoring, 1270 Urinary Ketone Testing, 1270 Self-Monitoring of Blood Glucose, 1271

DIAGNOSTIC SUMMARY Elevated blood glucose is determined by the following: • Fasting (overnight): venous plasma glucose concentration greater than or equal to 126 mg/dL on at least two separate occasions. • Following ingestion of 75 g of glucose: venous plasma glucose concentration greater than or equal to 200 mg/dL at 2 hours postingestion and at least one other sample during the 2-hour test. • A random blood glucose level of 200 mg/dL or more plus the presence of suggestive symptoms. • Classic symptoms of polyuria, polydipsia, and polyphagia. • Fatigue, blurred vision, poor wound healing, periodontal disease, and frequent infections are often manifesting symptoms as well in type 2 diabetes. 

GENERAL CONSIDERATIONS Diabetes is a chronic disorder of carbohydrate, fat, and protein metabolism characterized by fasting elevations of blood glucose levels and a greatly increased risk of cardiovascular disease, renal disease, and neuropathy. Diabetes is divided into two major categories: types 1 and 2. Type 1 diabetes (T1DM) occurs most often in children and adolescents. For this reason, it is often referred to as juvenile-onset diabetes. About 5% to 10% of all diabetic patients have T1DM. (Box 165.1 lists the major complications of diabetes.)

1262

Type 1 Diabetes and Self-Monitoring of Blood Glucose, 1271 Type 2 Diabetes and Self-Monitoring of Blood Glucose, 1271 C-Peptide Determination, 1272 Physician Monitoring, 1272 The Complications of Diabetes, 1272 Acute Complications, 1272 Chronic Complications, 1274 Contributors to the Long-Term Complications of Diabetes, 1274 Therapeutic Considerations, 1275 Diet Therapy in Managing Diabetes, 1275 Psychological Support in Diabetes, 1276 Exercise and Diabetes, 1277 Nutritional Supplements, 1277 Recommendations for Specific Chronic Complications, 1283 Therapeutic Approach, 1285 Supplementation for Type 1 Diabetes, 1285 Supplementation for Type 2 Diabetes, 1285 Additional Supplements for the Prevention and Treatment of Diabetic Complications, 1286

T1DM is an autoimmune disease caused by the destruction of the beta cells of the pancreas, which manufacture insulin. Positive antibodies against beta cells or insulin occur in 75% of patients with T1DM. Why the immune system is activated to attack the pancreas is not fully clear, but viral infection, food sensitivities, and chemical or free radical damage are likely possibilities, combined with genes that may predispose to T1DM. These individuals will require lifelong insulin for the control of blood glucose levels. The individual with T1DM must learn how to manage blood glucose levels on a day-by-day basis, modifying insulin types and dosages as necessary according to meals eaten, liver production of glucose, and the results of regular blood glucose testing. Type 2 diabetes (T2DM) historically has had an onset after age 40 in overweight individuals, but today it is seen even in pediatric patients because of the obesity epidemic, which affects all age groups in America. It is generally thought that up to 90% of all those with diabetes have T2DM. Initially, insulin levels are typically elevated in T2DM, indicating a loss of sensitivity to insulin by the body’s cells. Obesity is a major contributing factor to this loss of insulin sensitivity. Approximately 90% of individuals categorized as having T2DM are obese. The achievement of an ideal body weight in these patients is often associated with the restoration of normal blood glucose levels. Even if T2DM has progressed to the point where insulin deficiency is present, weight loss nearly always results in significant improvements in blood glucose control and dramatic reductions in other health risks, such as cardiovascular disease (Table 165.1).

CHAPTER 165 

BOX 165.1  Major Complications of Diabetes • Cardiovascular disease: Adults with diabetes have death rates from cardiovascular disease about two to four times higher than that for adults without diabetes. • Hypertension: About 75% of adults with diabetes have high blood pressure. • Retinopathy: Diabetes is the leading cause of blindness among adults. • Renal disease: Diabetes is the leading reason for dialysis treatment, accounting for 43% of new cases. • Neuropathy: About 60% to 70% of people with diabetes have mild to severe forms of nervous system damage. Severe forms of diabetic nerve disease are a major contributing cause of lower-extremity amputations. • Amputations: More than 60% of lower-limb amputations in the United States occur among people with diabetes. • Periodontal disease: Almost one third of people with diabetes have severe periodontal (gum) disease. • Pain: Many people with diabetes fall victim to chronic pain due to conditions such as arthritis, neuropathy, circulatory insufficiency, or muscle pain (fibromyalgia). • Depression: This is a common accompaniment of diabetes. Clinical depression can often begin to occur even years before diabetes is fully evident. It is difficult to treat in those with poorly controlled diabetes. • Autoimmune disorders: Thyroid disease, inflammatory arthritis, and other diseases of the immune system commonly add to the suffering of people with diabetes.

TABLE 165.1  Differences Between Type 1

and Type 2 Diabetes Features

Type I

Usually younger than 40 years Proportion of all diabetics 90% Common Slow Common Normal to high initially, decreased after several years Often Usually not required

Occasional Always

T2DM is a disease characterized by progressive worsening of glycemic control, which starts with mild alterations in postprandial glucose homeostasis followed by an increase in fasting plasma glucose and often ultimately a lack of production of insulin and the need for insulin therapy. There are other types of diabetes, such as latent autoimmune diabetes of the adult, sometimes termed type 1.5. This is a slower-onset autoimmune type of diabetes that occurs later in life, often after people reach 35 years of age. Diabetes may also occur as a result of chronic pancreatitis and other insults to the pancreas. Gestational diabetes, another type, affects about 4% of all pregnant women, adding up to about 135,000 cases in the United States each year. This occurs in women who were not diabetic before they became pregnant but developed diabetes during pregnancy. Gestational diabetes occurs more frequently among African Americans, Hispanic/Latino Americans, and American Indians. It is also more common among obese women and women with a family history of diabetes. After pregnancy, 5% to 10% of women with gestational diabetes are found to have T2DM. Women who have had gestational diabetes have a 20% to 50% chance

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of developing diabetes in the following 5 to 10 years. The least common types of diabetes are genetic disorders, such as neonatal diabetes and mature-onset diabetes of youth, which are generally due to faulty genes causing impaired insulin function.

Prediabetes and Metabolic Syndrome Prediabetes (also called “impaired glucose tolerance”) is characterized by a glycosylated hemoglobin (A1c) from 5.7% to 6.4%, a fasting glucose between 100 and 125 mg/dL, and/or a postprandial glucose of 140 to 199 mg/dL. It is the first step in insulin resistance and estimated to affect more than 60 million Americans. Many people with prediabetes will go on to develop full-blown T2DM despite the fact that prediabetes is usually reversible and, in most cases, diabetes can be completely avoided through dietary and lifestyle changes. Factors implicated in contributing to prediabetes, insulin resistance, and the progression to T2DM include a diet high in refined carbohydrates, particularly high-fructose corn syrup; an elevated intake of saturated fats; overeating due to increased portion sizes of food; increases in inflammatory markers; lack of exercise; industrial pollution; abdominal weight gain; hormonal imbalances; inadequate sleep; and nutritional deficiencies. Research increasingly indicates that prediabetes is accompanied by serious health risks, especially an increased risk for cardiovascular disease. Individuals with prediabetes often meet the criteria for the metabolic syndrome (MetS). This is a cluster of factors that together carry a significantly greater risk for cardiovascular disease and the development of T2DM. They include the following: • Greater waist-to-hip ratio • Two of the following: • Triglycerides greater than 150 mg/dL • High-density lipoprotein cholesterol (HDL-C) less than 40 mg/ dL for men, less than 50 mg/dL for women • Blood pressure equal to or greater than 130/85 mm Hg • Fasting plasma glucose equal to or greater than 100 mg/dL By this definition and using data from the National Health and Nutrition Examination Survey (2012), the prevalence of MetS in the United States is 34.2% among men and women aged 18 and above.1 Among adolescents and using a similar definition, approximately 5.8% meet the established criteria.2 In addition to an elevated risk for cardiovascular disease and diabetes, individuals with MetS report poorer health-related quality of life, both physically and mentally.3 

DIAGNOSTIC CONSIDERATIONS The classic symptoms of T1DM are frequent urination, weight loss, impaired wound healing, infections, and excessive thirst and appetite. Such individuals may suffer from diabetic ketoacidosis upon diagnosis, and they are usually lean in presentation. In T2DM, the symptoms are generally milder and may go unnoticed. For that reason and others, many people with T2DM do not even know that they have the disease. Abdominal obesity, fatigue, blurred vision, poor wound healing, periodontal disease, and frequent infections are often manifesting symptoms of T2DM. The standard method for diagnosing diabetes involves the measurement of blood glucose levels. The initial measurement is generally a fasting blood glucose taken after the patient has avoided food for at least 10 hours but not more than 16. The normal reading is between 70 and 99 mg/dL. If a person has a fasting blood glucose measurement greater than 126 mg/dL (7 mmol/L) on two separate occasions, the diagnosis is diabetes. As mentioned previously, a fasting glucose greater than 100 but less than 126 mg/dL is classified as prediabetes. A postprandial and a random glucose determination are also helpful in diagnosing diabetes. A postprandial measurement is usually made 1 to 2 hours after a meal, whereas a random measurement is

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TABLE 165.2  Criteria for Response to the

Glucose Tolerance Test Type

Criteria

Normal

No elevation > 160 mg/dL (9 mmol/L); 180 mg/dL (10 mmol/L) during first hour, 200 mg/dL (11.1 mmol/L) or higher at end of first hour, 150 mg/dL (8.3 mmol/L) or higher at end of second hour

Flat Prediabetic Diabetic

one that is made at any time during the day without regard to the time of the last meal. Any reading greater than 200 mg/dL (11 mmol/L) is considered indicative of diabetes (Table 165.2).

Glycosylated Hemoglobin The measurement glycosylated HgbA1c is a valuable laboratory test for evaluating long-term blood glucose levels. Proteins that have glucose molecules attached to them (glycosylated peptides) are elevated severalfold in diabetic patients. Normally, about 4.6% to 5.7% of hemoglobin is combined with glucose. An HgbA1c from 5.7% to 6.4% indicates prediabetes. An HgbA1c of 6.5% or higher, particularly when done as a screening test, can diagnose diabetes and is particularly helpful in patients with nondiagnostic fasting blood sugar levels. Nonetheless, it is best coupled with a fasting blood glucose measurement and a 2-hour postprandial glucose level for a more accurate diagnosis. Because the average life of a red blood cell (RBC) is 120 days, the HgbA1c assay represents time-averaged values for blood glucose over the preceding 2 to 4 months. An HgbA1c at 5% indicates that the glucose median for the previous 3 months was around 100 mg/dL; for each digit of elevation in the percentage, a rough addition of 35 mg/dL is followed. Thus an HgbA1c of 7% means that on average over the preceding 3 months, the patient’s blood glucose was 170 mg/dL. The HgbA1c index is extremely valuable in providing a simple, useful method for assessing the effectiveness of treatment as well as patient compliance; it should be checked every 3 to 6 months.4

Criteria for the Screening and Diagnosis of Diabetes4 Prediabetes A1c FPG OGTT RPG aFor

5.7–6.4%a 100–125 mg/dL (5.6–6.9 mmol/L)a 140–199 mg/dL (7.8–11.0 mmol/L)a —

Diabetes ≥6.5%b ≥126 mg/dL (7.0 mmol/L)b ≥200 mg/dL (11.1 mmol/L)b ≥200 mg/dL (11.1 mmol/L)c

all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range. bIn the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. cOnly diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. FPG, Fasting plasma glucose; OGTT, oral glucose tolerance test; RPG, random plasma glucose. 

RISK FACTORS FOR TYPE 1 DIABETES In T1DM the insulin-producing cells of the pancreas are ultimately destroyed, in most cases by the body’s own immune system, but what triggers this destruction can vary from one case to another. Genetic factors may predispose a person to damage to the insulin-producing cells through either impaired defense mechanisms, immune system sensitivity, or a defect in tissue-regeneration capacity. The entire set of genetic factors linked to T1DM have been termed “susceptibility genes” because they modify the risk of diabetes but are neither necessary nor sufficient for disease to develop.5 Rather than acting as the primary cause, the genetic predisposition simply sets the stage for the environmental or dietary factor to initiate the destructive process.6 The very term predisposition clearly indicates that something else must occur: less than 10% of those with increased genetic susceptibility for T1DM actually develop the disease.7 In detailed studies, the concordance rate for developing T1DM in identical twins was only 23% in one study8 and 38% in another.9 If one twin develops T1DM after age 24, the concordance rates drops all the way down to 6%, meaning that the other twin is at very low risk for developing the disease. These results and others indicate that in most cases, even where there is a true genetic predisposition, environmental and dietary factors may be more important in determining whether diabetes will develop.10 Additional evidence supporting the need to focus on dietary and environmental triggers follows: • There has been a threefold to tenfold increase in the number of people with T1DM throughout the world over the past 40 years. Such a rise simply cannot be explained by an increased number of people genetically predisposed to T1DM. Changes to the human genetic code across large populations take more than one generation.11 • The rate of T1DM can increase dramatically when children in areas where T1DM is relatively rare move to developed countries.12 For example, the rate of T1DM increased by nearly fourfold in one 10-year period in children of Asian origin moving to Great Britain, and the rate increased more than sevenfold in Polynesians migrating to New Zealand.13,14 Genetic factors cannot explain such a rapid change.

Environmental and Dietary Risk Factors Accumulating data indicate that abnormalities of the gut immune system and microbiome may play a fundamental role in the development of the immune attack on beta cells and the subsequent development of T1DM.15 The intestinal immune system serves a vital role in processing the many food and microbial antigens to protect the body from infection and allergy. What appears to happen in the development of some cases of T1DM is the development of antibodies by the gut immune system that ultimately attack the beta cells. Possibly an underlying factor that may contribute to T1DM is poor protein digestion. Poorly digested dietary proteins can cross-react with antigens on or within the beta cells of the pancreas. In humans, two proteins that have had the highest degree of incrimination are those found in milk (which contains bovine serum albumin and bovine insulin) and wheat (which contains gluten). For example, dietary bovine insulin differs from human insulin by only three amino acids. If a person develops antibodies to bovine insulin, there is a good chance that these antibodies will also attack their own insulin. In addition to causing antibody-mediated destruction of the beta cells, bovine insulin is able to activate T cells in those predisposed to diabetes in a manner that can also lead to beta-cell destruction by direct attack from T-killer cells. Strong evidence implicates dietary factors like cow’s milk and gluten as important triggers of the autoimmune process that leads to T1DM. In contrast, breastfeeding has been identified as an important factor in

CHAPTER 165  establishing proper intestinal immune function and reducing the risk of T1DM. It is well known that breastfeeding confers a reduction in the risk of food allergies as well as better protection against both bacterial and viral intestinal infections. In case-controlled studies, patients with T1DM were more likely to have been breastfed for less than 3 months and to have been exposed to cow’s milk or solid foods before 4 months of age. A critical review and analysis of all relevant citations in the medical literature indicate that early cow’s milk exposure may increase the risk by about 1.5 times.14,16 In addition, although the risk of diabetes associated with exposure to cow’s milk was first thought to relate only to intake during infancy, additional studies showed that ingestion at any age may increase the risk of T1DM. There is also considerable evidence that sensitivity to gluten—the major protein component of wheat, rye, and barley—may also play a role. Gluten sensitivity produces celiac disease, another autoimmune disorder. Celiac disease, like T1DM, is associated with abnormalities in intestinal immune function. And as in the case of diabetes, breastfeeding appears to have a preventive effect, whereas the early introduction of cow’s milk is believed to be a major causative factor. The risk of developing T1DM is higher in children with celiac disease. Not surprisingly, the highest level of antibodies to cow’s milk proteins is found in people with celiac disease.17

Enteroviruses and Type 1 Diabetes Population-based studies, as well as prospective studies, have strengthened the hypothesis that T1DM can be the result of viral infection both during pregnancy and after birth.18,19 A working theory in this regard is that the immune system becomes slightly confused as to which proteins to attack—the food-based ones such as those from dairy or gluten or the similar proteins on the pancreatic beta cells or insulin. When the person then has a viral infection, the increased stimulation of the immune system is the key that prompts it to become more active, and those confused immune cells begin to damage the pancreas. Gastrointestinal infections due to enteroviruses (e.g., polioviruses, coxsackieviruses, echoviruses) and rotavirus are common, especially in children. All of these viruses replicate in the gut and stimulate the intestinal immune system, which may then activate the insulin-specific immune cells to seek out and destroy beta cells. These viruses and others are also capable of infecting pancreatic beta cells, causing the leukocytes to attack and destroy the beta cells in an attempt to kill the virus. Gastrointestinal viral infections may also increase intestinal permeability and enhance the antibody response to dietary bovine insulin as a result of increased absorption of the intact protein. The severe “leaky gut”—or increased permeability of the small intestine that occurs during and for some time after rotavirus infections (one of the most common causes of acute diarrheal illness in children)—exposes the gut-associated immune cells to large quantities of intact protein. 

Vitamin D Deficiency Cod liver oil may offer significant protection against the development of diabetes because of its high content of vitamin D. The use of cod liver oil became popular during the 1890s to treat rickets, a vitamin D–deficiency disease characterized by an inability to calcify the bone matrix, resulting in softening of the skull bones, bowing of the legs, spinal curvature, and enlarged joints. Beginning in the 1930s, vitamin D was added to milk at a level of 100 IU per 8 oz. As a result, rickets is now uncommon in most developed countries. Emerging evidence indicates that vitamin D supplementation from cod liver oil and other sources during early childhood can prevent not only rickets but also T1DM.20 In fact, vitamin D fortification may offset some of the “diabetogenic” effect of cow’s milk, but the dosage level in milk may not be sufficient to do so; the level that was shown to be

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protective was about 2000 IU—much higher than the amount typically ingested from the consumption of vitamin D–fortified milk. The most extensive study looking at vitamin D and T1DM enrolled all pregnant women in northern Finland who were due to give birth in 1966 (more than 12,000 women), and their children were then monitored until December 1997.21 Final analysis of 10,366 enrollees demonstrated that children who regularly took vitamin D, primarily from cod liver oil, had an 80% reduced risk of developing T1DM, whereas those who had a vitamin D deficiency actually had a 300% increased risk of developing the disease. One study found that the use of vitamin D from cod liver oil during pregnancy significantly reduced the frequency of T1DM in the offspring.22 Furthermore, studies looking at vitamin D status in the blood of newly diagnosed individuals with T1DM have found much lower levels of the vitamin in these patients than in healthy controls. Because vitamin D can be produced in the body by the action of sunlight on the skin, lack of sun exposure during childhood may also play a role and partially explain the higher T1DM rates in northern countries. Vitamin D in recent research has been shown to prevent autoimmune conditions, including those that attack beta cells, from developing in the body, and observational studies have shown a dose-dependent degree of protection.23 This research indicates that ensuring adequate vitamin D supplementation during pregnancy and early childhood may reduce the risk of T1DM. Vitamin D is important for the normal development of the immune system. In addition, it has been shown that vitamin D inhibits some of the autoimmune reactions that target the beta cells. 

Omega-3 Fatty Acid Deficiency In addition to the strong case that can be made for vitamin D as a protective factor, an equally strong case can be made for the benefits of the omega-3 fatty acids in cod liver oil and other fish oils. Human studies have shown that when essential fatty acids (EFAs) are given, the onset of T1DM was significantly reduced. Also, higher levels of n-3 polyunsaturated fatty acids in RBCs have also been associated with reduced risk.24 For one thing, cod liver oil also provides both EPA and DHA, which are vital EFAs in humans. Other studies support the benefit of supplementing EFAs in pregnant women and children. The mechanisms responsible for this effect may be related to improved cell membrane function, leading to enhanced antioxidant status and the reduced formation of inflammatory compounds called cytokines.25 

Nitrates Clear links between increased levels of nitrates (from both dietary sources and water) and an increased rate of T1DM have been established. Nitrates are produced by agricultural runoff from fertilizers and are found in cured or smoked meats such as ham, hot dogs, bacon, and jerky to keep the food from spoiling. Nitrates react within the body to form compounds known as nitrosamines. (Note: The U.S. Department of Agriculture [USDA] requires all manufacturers of processed meats to add vitamin C to their products to prevent the formation of nitrosamines.) Nitrates and nitrosamines are known to cause diabetes in animals. Infants and young children are believed to be particularly vulnerable to the harmful effects of nitrate exposure. One of the most alarming features of T1DM is that it is becoming much more prevalent, with a current growth rate of 3% per year worldwide. Some areas have been hit particularly hard, such as Finland, Great Britain, Canada, and the United States. Increased nitrate exposure may be a key factor; the nitrate levels in ground and surface waters of agricultural regions have increased over the past 40 years owing to the use of nitrogen fertilizers. Nitrate contamination occurs in geographical patterns related to the amount of nitrogen contributed by fertilizers, manure, and airborne sources such as automobile and

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industrial emissions. Nitrate exposure may explain why some geographical pockets have substantially higher rates of T1DM.26,27 Circumstantial evidence from population-based studies also suggests that a higher dietary intake of nitrates from smoked/cured meats is associated with a significantly higher risk for T1DM. These foods severely stress body defense mechanisms and are to be avoided. The habit of feeding children hot dogs, cold cuts, and ham would be a good one for parents to break. Health food stores now carry nitrate-free alternatives to these toxic food choices. Also, investing in a high-quality water purifier is good insurance against ingesting nitrate-contaminated drinking water. 

EARLY TREATMENT AND POSSIBLE REVERSAL OF TYPE 1 DIABETES Early intervention in T1DM designed to affect the autoimmune or oxidative process theoretically may be capable of lengthening the “honeymoon” phase or even completely reversing the process. This goal appears to have two candidates: niacinamide and epicatechin. Removing gluten and dairy from the diet and supporting gut health as well as immune system balance are also important considerations.

Niacinamide Niacinamide, also called nicotinamide, has been shown to prevent some of the immune-mediated destruction of the pancreatic beta cells and may actually help reverse the process in some patients.28,29 Observations that niacinamide can prevent the development of T1DM in experimental animals led to several pilot clinical trials that initially confirmed these observations and suggested that if given soon enough at the onset of diabetes, niacinamide could help restore beta cells or at least slow down their destruction. In one of the first pilot studies of people newly diagnosed with T1DM, seven patients were given 3 g of niacinamide daily, and nine were given a placebo. After 6 months, five patients in the niacinamide group and two in the placebo group were still not taking insulin and had normal blood glucose and HgbA1c. At 12 months, three patients in the niacinamide group but none in the placebo group were in clinical remission.30 The results of this pilot study and others suggest that niacinamide can prevent T1DM from progressing in some patients if given soon enough at the onset of diabetes by helping restore beta cells. As of 2004, there had been 12 studies of niacinamide treatment in recent-onset T1DM or T1DM of less than 5 years’ duration and residual beta-cell mass. Ten of these were double-blind placebo-controlled studies, of which half showed a positive effect compared with placebo in terms of prolonged non–insulin-requiring remission, lower insulin requirements, improved metabolic control, and increased beta-cell function as determined by secretion of a substance known as C-peptide. The main differences between the positive and negative studies in recent-onset T1DM were older age and higher baseline fasting C-peptide in positive studies.31–34 Although some of the studies have shown positive results, it is important to point out that two large studies designed to evaluate the effectiveness of niacinamide in preventing the development of T1DM in high-risk individuals—such as siblings of children who developed T1DM or in individuals who already show elevations in antibodies directed against the beta cells—did not show niacinamide to be effective. The first of these, the German Nicotinamide Intervention Study, did not show much of an effect with 1.2 g of niacinamide daily, and results from the larger study, the European Nicotinamide Diabetes Intervention Trial, did not show benefit with dosages as high as 3 g a day.35,36 A possible shortcoming of these studies was the choice of a timed-released niacinamide. It is possible that such a formulation did

provide the peak levels of niacinamide required to block autoimmune mechanisms such as cytokine production.37 In the best-case scenario, niacinamide will likely work for only a few individuals with T1DM of recent onset. Nonetheless, the fact that some patients have had a complete reversal of their disease makes a trial of niacinamide worth the effort, especially because there is currently no reasonable alternative. The dosage recommendation is based on body weight: 25 to 50 mg of niacinamide for every 2.2 lb of body weight or a maximum dosage of 3 g/day in divided doses. Niacinamide is generally well tolerated and without side effects. In fact, no side effects have been reported in clinical trials in T1DM. It does not cause the flushing of the skin characterizing high dosages of niacin. However, because it could possibly harm the liver, a blood test for liver enzymes should be performed every 3 months to rule out liver damage. 

Epicatechin The second natural compound that may offer benefit is epicatechin. The line of research on its potential role in T1DM of recent onset began with examining the bark of the Malabar kino tree (Pterocarpus marsupium). This botanical medicine has a long history of use in India as a treatment for diabetes. Initially, epicatechin extracted from the bark was shown to prevent beta-cell damage in rats. Further research indicated that both epicatechin and a crude alcohol extract of P. marsupium were actually able to promote the regeneration of functional pancreatic beta cells in diabetic animals.38 Green tea (Camellia sinensis) extract appears to be a better choice than extracts of P. marsupium because the epicatechin content in a high-quality green tea extract is actually higher than that found in extracts of P. marsupium. Second, green tea extract exerts a broader range of beneficial effects. Green tea polyphenols also exhibit significant antiviral activity against rotavirus and enterovirus—two viruses suspected of causing T1DM.39 Last, green tea extract is considerably easier to find commercially than P. marsupium. Recommended dosages for children below age 6 is 50 to 150 mg; for those 6 to 12 years old, 100 to 200 mg; and for children older than 12 years old and adults, 150 to 300 mg. The green tea extract should have a polyphenol content of 80% and be decaffeinated. Although the focus in the research has been on the reversal of T1DM, epicatechin may have more meaningful effects in prevention; epicatechin effectively prevented T1DM in nonobese diabetic (NOD) mice. At 32 weeks of age, 66.7% of control mice had overt diabetes, whereas only 16.6% of epicatechin-treated mice became diabetic. Consistently, epicatechin-treated mice had significantly higher plasma insulin levels but lower glycosylated hemoglobin concentrations compared with control mice. Treatment with epicatechin elevates circulating anti-inflammatory cytokine interleukin-10 levels, ameliorates pancreatic insulitis, and improves pancreatic islet mass—all important factors that may help prevent T1DM by modulating immune function and thereby preserving islet mass. 

RISK FACTORS IN TYPE 2 DIABETES Several factors are involved in the development and progression of diabetes. The most well-accepted major risk factor for T2DM is obesity or, more precisely, excess body fat. Approximately 80% to 90% of individuals with T2DM are obese (a body mass index above 30). When adipocytes, particularly those around the abdomen, become full of fat, they secrete several biological products (e.g., resistin, leptin, tumor necrosis factor, free fatty acids, cortisol) that dampen the effect of insulin, impair glucose utilization in skeletal muscle, promote glucose production

CHAPTER 165  by the liver, and impair insulin release by pancreatic beta cells. Also important is that as the number and size of adipocytes increase, there is a reduction in the secretion of compounds that promote insulin action, including a novel protein produced by fat cells known as adiponectin. Adiponectin is associated not only with improved insulin sensitivity but also with anti-inflammatory activity; moreover, it lowers triglycerides and blocks the development of atherosclerosis, or hardening of the arteries. The net effect of these negative actions of fat cells is that they severely stress blood glucose control mechanisms while also leading to the development of the major complication of diabetes: atherosclerosis. Because of all these newly discovered hormones secreted by adipocytes, many experts now consider the adipose tissue a member of the endocrine system (e.g., the pituitary, adrenals, and thyroid).40 Measurements of blood levels of adiponectin and other hormones secreted by fat cells may turn out to be the most meaningful predictors of the likelihood of developing T2DM as well as gestational diabetes.41,42 In the early stages of the increased metabolic stress produced by the various secretions of adipocytes and the lack of adiponectin, blood glucose levels remain normal despite insulin resistance because pancreatic beta cells compensate by increasing insulin output. As metabolic stress increases and insulin resistance becomes more significant, the conventional explanation is that eventually the pancreas cannot compensate and elevations in blood glucose levels develop. As the disease progresses from insulin resistance to full-blown diabetes, the pancreas starts to “burn out” and produces less insulin. Avoiding this occurrence is a key therapeutic goal and is achievable with good diabetes care and if a patient’s HgbA1c remains at 5.7 or less. (See Box 165.2 for risk factors.)

Genetics of Type 2 Diabetes and Obesity

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1267

predisposition, but even with this strong tendency, the high rate of T2DM in this group is clearly related to diet and lifestyle. The Pima Indians living traditionally in Mexico still cultivate corn, beans, and potatoes as their main staples, plus a limited amount of seasonal vegetables and fruits such as zucchini squash, tomatoes, garlic, green pepper, peaches, and apples. The Pimas of Mexico also make heavy use of wild and medicinal plants in their diet. They work hard, have no electricity or running water in their homes, and walk long distances to bring in drinking water or wash their clothes. They use no modern household devices; consequently, food preparation and household chores require extra effort from the women. In contrast, the Pima Indians of Arizona are largely sedentary and follow the dietary practices of typical Americans. The results are astounding. Although roughly 16% of U.S. Native Americans have T2DM, 50% of Arizona Pimas have T2DM, and 95% of them are overweight or obese. T2DM is a rarity among the Mexican Pimas, and only about 10% can be classified as obese. The average difference in body weight between the Arizona and Mexican Pima men and women was more than 60 lb.44 Further evidence that diet and lifestyle appear to be able to overcome even the strongest genetic predisposition is shown by some of the intervention studies among Pima Indians. When these people were placed on a more traditional diet along with physical exercise, their blood glucose levels improved dramatically, and they lost weight. The focus right now, by various medical organizations such as the National Institute of Health, in dealing with the epidemic of diabetes and obesity among the Pima Indians is to educate children on the importance of exercise and dietary choices to reduce diabetes risk. 

Other Genetic and Racial Factors

In studies of identical twins, the concordance rate was between 70% and 90% for T2DM. This high concordance points to a strong genetic relationship. Data from family studies also provide additional support: children with one parent with T2DM have an increased risk of developing diabetes at some point in their lives. If both parents have the disease, the risk in offspring is nearly 40%. However, even with the strongest predisposition, diabetes can be avoided in most cases.43

Other racial and ethnic groups beside Pima Indians that have a higher tendency to develop T2DM include other Native Americans, African Americans, Hispanic Americans, Asian Americans, Australian Aborigines, and Pacific Islanders. It is important for all these higher-risk groups to learn that when they follow the traditional dietary and lifestyle practices of their original cultures, their rates of diabetes will be extremely low. It appears that these groups are simply highly sensitive to the “Western diet” and lifestyle. 

The Case of the Pima Indians

Diet, Exercise, Lifestyle, and Diabetes Risk

The Pima Indians of Arizona have the highest rate of T2DM and obesity anywhere in the world. Research has demonstrated a strong genetic

Findings from the U.S. government’s Third National Health and Nutrition Examination Surveys (NHANES) make it clear that diabetes is a disease of diet and lifestyle. Of individuals with T2DM, 69% did not exercise at all or did not engage in regular exercise, 62% ate fewer than five servings of fruits and vegetables per day, 65% consumed more than 30% of their daily calories from fat and more than 10% of total calories from saturated fat, and 82% were either overweight or obese.45 Insights into the independent role of the modern lifestyle versus diet and obesity in the development of T2DM can be gleaned from the Old Order Amish. These 30,000 or so individuals, whose ancestors

BOX 165.2  Risk Factors for Type 2 Diabetes

Mellitus

• Family history of diabetes (i.e., parent or sibling with type 2 diabetes) • Obesity • Increased waist-to-hip ratio • Age: increasing age is associated with increased risk, beginning at age 45 • Race/ethnicity (e.g., African American, Hispanic American, Native American/Canadian, Native Australian or New Zealander, Asian American, Pacific Islander) • Previously identified impaired fasting glucose or impaired glucose tolerance • History of gestational diabetes (diabetes during pregnancy) or delivery of a baby weighing more than 9 lb • Hypertension (blood pressure >140/90 mm Hg) • Triglyceride level >250 mg/dL • Low levels of adiponectin, elevated levels of fasting insulin • Polycystic ovary syndrome (to be considered in any adult woman who is overweight with both acne and infertility)

arrived on U.S. shores in the 18th century, maintain religious and cultural beliefs that preclude regular use of modern conveniences such as electrical appliances, telephones, and cars, and they have a physically active lifestyle. By comparison, the 200 million typical Americans living alongside them have, over the past 250 years, willingly adopted the advances of modern technology, making life less physically demanding. Although the typical Amish diet and rate of obesity do not differ from those of the typical American, the rate of diabetes among the Amish is considerably less—about 50% lower. Although the percentage of Amish with impaired glucose tolerance (prediabetes) is about the same as in other whites in America, apparently not as many Amish go on to develop diabetes. This suggests that physical activity has a

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protective effect against T2DM independent of obesity or percentage of body fat.46,47 Results from other studies corroborate this hypothesis. Lifestyle changes alone are associated with a 58% reduced risk of developing diabetes among those at high risk because they show evidence of impaired glucose tolerance (as based on results from the Diabetes Prevention Program—a large intervention trial of more than 1000 subjects). The two major goals of the program were a minimum of 7% weight loss/weight maintenance and a minimum of 150 min/week of physical activity similar in intensity to brisk walking.48

A Diet High in Refined Carbohydrates Dietary carbohydrates play a central role in the causes, prevention, and treatment of T2DM. In an effort to qualify carbohydrate sources as acceptable or not, two indices have been developed: the glycemic index (GI) and glycemic load (GL). The GI is a numerical value that expresses the rise in blood glucose after a particular food is eaten. The standard value of 100 is based on the rise seen with the ingestion of glucose. The GI ranges from about 20 for fructose and whole barley to about 98 for a baked potato. The insulin response to carbohydrate-containing foods is similar to the rise in blood sugar. The GI is often used as a guideline in dietary recommendations for people with either diabetes or hypoglycemia. In addition, eating foods with a lower GI is associated with a reduced risk for obesity and diabetes.49–51 One of the shortcomings of the GI is that it tells us only about the quality of the carbohydrates, not the quantity. Obviously, quantity matters too, but measurement of the GI of a food is not related to portion size. That is where the GL comes into play. The GL takes the GI into account but provides much more accurate information than the GI alone. The GL is calculated by multiplying the amount of carbohydrate in a serving of food by that food’s GI (compared with glucose) and then dividing it by 100. The higher the GL, the greater the stress on insulin. In Appendix 7, we provide the GI and GL for many common foods. Research studies are just starting to use the GL as a more sensitive marker for the role of diet in chronic conditions like diabetes and heart disease. The preliminary results are showing an even stronger link in predicting diabetes than the one shown for the GI.49,51 Researchers are also showing that a high-GL diet is also associated with an increased risk for heart disease. For example, when researchers from the Nurse’s Health Study used GL measures to assess the effect of carbohydrate consumption on women, they found that high-GL diets (and, by extension, high-GI foods and greater total carbohydrate intake) correlated with even more significantly greater risk for heart disease than the GI because of lower levels of protective HDL-C and higher triglyceride levels.52 Increased risk for diabetes and heart disease started, on average, at a daily GL of 161. Therefore we recommend using the information in Appendix 7 to help determine how to prevent the total daily GL from exceeding 150. Keep in mind that the GL is based on the stated serving size; the larger the serving size, the greater the GL. 

The Importance of Dietary Fiber in Reducing the Risk of Developing Diabetes Population studies, as well as clinical and experimental data, show diabetes to be one of the diseases most clearly related to an inadequate intake of dietary fiber. Different types of fiber possess different actions. The type of fiber that exerts the most beneficial effects on blood sugar control is the water-soluble form. Included in this class are hemicelluloses, mucilages, gums, and pectins. These types of fiber are capable of slowing down the digestion and absorption of carbohydrates, thereby preventing rapid rises in blood sugar. They are also associated with increasing the sensitivity of tissues to insulin and improving the uptake

of glucose by the muscles, liver, and other tissues, thereby preventing a sustained elevation of blood sugar.53,54 Particularly good sources of water-soluble fiber are legumes, oat bran, nuts, seeds, psyllium seed husks, pears, apples, and most vegetables. Large amounts of plant foods must be consumed to obtain adequate levels of dietary fiber, although beans, peas, and legumes are overall the best sources for high fiber intake in relatively easy amounts to ingest. Even the simple change from white flour products to wholegrain versions is associated with a reduced risk for T2DM55,56; our recommendation is to consume at least 35 g of fiber a day from various food sources, especially vegetables. Fiber supplements can also be taken to achieve greater effects in lowering the GI. 

The Wrong Types of Fats Dietary fat also plays a central role in the likelihood of developing T2DM. Large controlled trials have shown that a reduction of fat intake as part of a healthy lifestyle, combined with weight reduction and exercise, reduces the risk for T2DM. However, more important than the amount of fat in the diet is the type of fat consumed.57 The types of dietary fats linked to T2DM include saturated fats and trans fatty acids (partially hydrogenated vegetable oils) taken in large amounts along with a relative insufficiency of monounsaturated and omega-3 fatty acids. One of the key reasons why dietary fats appear to be related to the risk for T2DM is that they determine cell membrane composition. That is, a “bad fat” pattern leads to reduced membrane fluidity, which in turn causes reduced insulin binding to receptors on cellular membranes, reduced insulin action, or both. Particularly harmful to cell membrane function are margarine, vegetable oil shortening, and other foods containing trans fatty acids and partially hydrogenated oils. These fatty acids interfere with the body’s ability to use important essential fatty acids (EFAs). One study estimated that by substituting polyunsaturated vegetable oils for margarine containing partially hydrogenated vegetable oil, the likelihood of developing T2DM could be reduced by 40%.58 In contrast to the dampening of insulin sensitivity caused by margarine and saturated fats, clinical studies have shown that monounsaturated fats and omega-3 oils improve insulin action.59 Adding further support is the fact that population studies have also indicated that the frequent consumption of monounsaturated fats such as olive oil, raw or lightly roasted nuts and seeds, nut oils, and omega-3 fatty acids from fish protect against the development of T2DM. Healthy omega-3 fish include wild salmon, trout, sardines, halibut, and herring. All of this evidence indicates that altered cell membrane composition and fluidity play a critical role in the development of T2DM. One of the most useful food groups to reduce the risk of T2DM is nuts. Studies have shown that consumption of nuts is inversely associated with the risk of T2DM, independent of known risk factors for T2DM, including age, obesity, family history of diabetes, physical activity, smoking, and other dietary factors.60 In addition to providing beneficial monounsaturated and polyunsaturated fats that improve insulin sensitivity, nuts are also rich in fiber and magnesium and have a low GI. Higher intakes of fiber and magnesium and foods with a low GI has been associated with a reduced risk of T2DM in several population-based studies. Eating mostly raw or lightly roasted fresh nuts and seeds rather than commercially roasted and salted nuts and seeds should be advocated. 

Low Intake of Antioxidant Nutrients Cumulative free-radical damage leads to cellular aging and is a major factor contributing to T2DM as well as many other chronic degenerative diseases. Several large population-based studies have shown that

Diabetes Mellitus Types I and II

One of the hallmark features of T2DM is the presence of higher levels of free radicals and prooxidants,68 particularly an increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS).69 These compounds are also activated by high blood glucose and elevated levels of saturated fat and, as already mentioned, are produced in the abdominal fat cells of individuals who are overweight or obese. These compounds greatly stress antioxidant mechanisms; they directly oxidize and damage cellular components such as DNA, proteins, and cell membrane fatty acids. In addition to their ability to directly inflict damage on these structures, ROS and RNS indirectly induce damage to tissues by activating several inflammatory compounds, such as nuclear factor-kappa B, which ultimately leads to both insulin resistance and impaired insulin secretion. 

250

Chemical Production

7

Diabetes Prevalence

6 5

200

4 150 3 100

2

50

1

0 1940

1950

1960

1970 1980 Year

1990

2000

0 2010

Fig. 165.1 The diabetes epidemic correlates with the release of persistent organic pollutants (POPs) into the environment. (From Ionnou GN, Bryson CL, Boyko EJ. Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes. J Diabetes Complications. 2007;21[6]:363–370.)

12

Odds ratio

Free Radicals and Diabetes

300 Synthetic Organic Chemical Production (billions of kilograms)

the higher the intake of fruit and vegetables, the better blood glucose levels are controlled and the lower the risk for T2DM.61 Many factors could explain this inverse correlation. Fruits and vegetables are good sources of fiber and also provide many nutrients and antioxidants. Even something as simple as the regular consumption of salads is associated with a reduced risk for T2DM.62 Studies looking at levels of individualized antioxidants have also shown similar inverse correlations—the higher the level of vitamin C, vitamin E, or carotenes, for example, the lower the risk for T2DM.63– 65 Likewise, the lower the levels of antioxidants and higher the levels of fats damaged by free radicals (lipid peroxides), the greater the risk for T2DM.66 In one study, 944 men 42 to 60 years of age were followed closely for 4 years. None of them had diabetes at the beginning of the study. At the end of this time, 45 men had developed diabetes. The researchers found that a low vitamin E concentration was associated with 3.9-fold (390%) increased risk for T2DM in the study subjects.67 

1269

Diabetes Prevalence (%)

CHAPTER 165 

8

PCB153 HpCDD OCDD Oxychlordane trans-Nonachlor DDE

4

Environmental Toxins

Persistent Organic Pollutants Persistent organic pollutants (POPs) include such chemical compounds as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), hexachlorobenzene (HCB), organophosphates, dichlorodiphenyldichloroethylene (DDE), and bisphenol A. These compounds have been linked to the development of T2DM. In addition, research indicates that the body load of POPs is not only a significant predictor of T2DM but may also be a more significant risk factor than obesity.70 Individuals in the top quintile of exposure to six common POPs have a 37.7-fold increased risk of diabetes—much stronger than any other known risk factor. Because many POPs block insulin receptor sites, decrease glucose transporter type 4 (GLUT-4) activity in muscles, and decrease insulin production, a causal relationship appears highly probable. Beginning in the 1960s, the production of synthetic organic chemicals began to escalate along with the incidence of diabetes (Fig. 165.1). The total load of toxicants may be the strongest contributing factor in the development of diabetes, with data so compelling that some researchers now label these toxicants as “diabetogens.” More convincing is the correlation between body load of POPs and the risk of metabolic syndrome, as shown in Fig. 165.2. The association is synergistic. When the relationship between POP levels and diabetes risk is examined, the case becomes even more compelling. Those in the top 10% of transnonachlor level, a common termiticide used in North America for decades, have a remarkable twelvefold increased risk of developing diabetes. Those with levels of

90th 25th 75th 50th Exposure category Fig. 165.2 Diabetes risk (odds ratio [OR]) for individual persistent organic pollutants (POPs) according to percentiles. Blue rectangle, PCB153; red rectangle, HpCDD; yellow rectangle, OCDD; green rectangle, oxychlordane; pink rectangle, trans-nonachlor; purple rectangle, DDE. Joseph Pizzorno, ND, Is the Diabetes Epidemic Primarily Due to Toxins?, Integr Med (Encinitas). 2016;15(4):8–17. Ref

organochlorine pesticides in the top quartile have an odds ratio of 5.3 for metabolic syndrome.71 Unfortunately, direct measurement of POP levels is difficult and very expensive. However, a good indirect measure is gamma-glutamyltransferase (GGTP). An elevated level of GGTP is a strong predictor of diabetes risk. Those with levels above 40 IU/L have a twentyfold increased risk.72 

Arsenic Arsenic exposure occurs primarily through diet and water. A surprising 13 million people in the United States use public water that exceeds the Environmental Protection Agency (EPA) limit of 10 ug/L. There is a direct correlation between the amount of arsenic in a person’s body and the risk of diabetes. In this case the primary mechanism appears to be the result of damaged pancreatic beta cells with resultant decrease insulin production.73

1270

SECTION 6 

Diseases

Arsenic has been shown to increase diabetes risk in a dose-dependent fashion. Comparing participants at the 80th versus the 20th percentiles, the odds ratios (ORs) for T2DM were 3.58 for the total level of arsenic, 1.57 for dimethylarsenate, and 0.69 for arsenobetaine.74 

Bisphenol A and Phthalates Higher urinary bisphenol A (BPA) concentrations are associated with type 2 diabetes, with an OR of 1.39 per 1-standard-deviation increase in BPA concentration.75 BPA blocks insulin receptor sites resulting in insulin resistance. This increases the incidence of diabetes as well as obesity, especially the accumulation of visceral fat. The threshold for doubling the risk for diabetes is 5.0 ug/L urine. Phthalates, such as di-2-ethyl-hexl phthalate, diethyl phthalate, dibutyl phthalate, dimethyl phthalate, dibenzyl phthalate, and diisononyl phthalate, are associated with the development of T2DM and obesity by interfering with various cell-signaling pathways involved in weight and glucose homeostasis.76 Mitochondrial inhibition by phthalates likely contributes significantly to their role in obesity and diabetes. 

Ambient Air Pollutants A 3+ year study of overweight and obese Latino children from Los Angeles, California, showed significant effects of elevated NO2 and particulate matter (PM) with an aerodynamic diameter of less than 2.5 (PM2.5) on insulin homeostasis and beta-cell function that were independent of body fat percentage.77 Epidemiological studies have also shown that greater exposure to NO2 and PM2.5 is associated with a greater risk for T2DM in adults.78 

Lifestyle Management Versus Drugs to Prevent Type 2 Diabetes Several well-designed large trials have shown that lifestyle and dietary modifications can be used to effectively prevent T2DM. That fact has not dissuaded drug companies from sponsoring studies attempting to prevent diabetes with drugs. However, the degree of prevention with drugs pales in comparison with that of diet and lifestyle. For example, in one of the most celebrated studies, 3234 subjects with impaired glucose tolerance (prediabetes) were randomly assigned to be in a group receiving a placebo, the blood glucose–lowering drug metformin (850 mg twice daily), or a lifestyle modification program with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The average follow-up was 2.8 years. The incidence of diabetes was 11, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence of diabetes by 58% and metformin by 31% compared with placebo. Clearly, the lifestyle intervention was significantly more effective than metformin—a drug with sometimes serious side effects.79

Environmental Toxicity Given the fact that environmental pollutants can increase the risk of developing T2DM, steps can be taken to reduce patients’ exposure to them. This can be done, for example, by eating organic foods, using natural cleaning agents in the home, and avoiding chemical pesticides. These are all valid steps in preventing environmental toxins undermining the regulation of insulin. 

CLINICAL MONITORING OF DIABETES Knowledge and awareness are the greatest allies of people with diabetes. An individual with diabetes who makes a strong commitment to learning about his or her condition and accepts the lead role in a carefully supervised monitoring program that breaks away from the standard

recommended by the American Diabetes Association (ADA) greatly improves the likelihood that he or she will lead a long and healthy life. On the other hand, individuals who remain blissfully ignorant about their disease and refuse to undergo regular testing or self-monitoring are far more likely to face years of unnecessary suffering and, more often than not, catastrophic health problems. Unless it is properly managed and supervised, diabetes can be viewed as a state of biochemical and hormonal anarchy that will lead to organ injury and accelerated aging. Many of the complex control systems that faithfully govern and protect the body are damaged in the diabetic individual. For such a person to regain control, he or she must learn how to maintain an intimate awareness of blood sugar, risk factors for atherosclerosis (hardening of the arteries), blood pressure, body mass index, level of fitness, and other factors that determine the risk of developing diabetic complications and experiencing an erosion of his or her quality of life. Fortunately, diabetic patients who do develop a keen awareness of these risk factors through regular testing and a properly supervised self-monitoring program are also those who are much more likely to benefit from changes in lifestyle: diet, supplements, and when necessary, medications.

Urinary Glucose Monitoring The measurement of glucose in the urine is now entirely passé. Until the mid-1970s, the only option that diabetic patients had to monitor blood glucose was indirectly through urine glucose testing. Normally, the kidneys are able to conserve all of the glucose in the blood that they constantly filter. However, if blood glucose gets too high, the kidneys become unable to conserve all of the glucose, which then begins to appear in the urine. Because the average diabetic patient’s kidneys can completely conserve glucose until the blood glucose reaches about 200 to 250 mg/dL (10 mmol/L), a negative urine glucose reading indicates that the blood glucose since the time of the previous voiding has been less than 200 to 250 mg/dL (10 mmol/L). Therefore the measurement of glucose in the urine is only a crude measurement of blood glucose control and is completely worthless in detecting severe hypoor hyperglycemia.80 Thus urinary glucose monitoring is of little value in determining the success of blood glucose control, and it does not provide adequate feedback when lifestyle, diet, or other treatments are adjusted. These days, all diabetic patients should own a glucometer and know how to test their own blood glucose levels. 

Urinary Ketone Testing In any circumstance when the body must derive its primary source of energy from fat, ketones are produced as a by-product. If the level of ketone production is high enough, ketones appear in the urine. In the patient with T1DM or T2DM who cannot produce any innate insulin, ketones appear in the urine when there is a severe deficiency in or activity of insulin. In general this is associated only with T1DM because the vast majority of patients with T2DM do not develop ketoacidosis. This can occur if a patient with insulin-dependent diabetes accidentally or purposefully forgets to take insulin. It can also occur when such a patient becomes ill or injured or is given high doses of cortisone-related drugs. All of these phenomena may result in a severe loss of insulin effectiveness, resulting in the cells’ inability to take up and use glucose. In such circumstances, blood glucose rises to high levels, high amounts of fat are used by cells that cannot take in glucose, and the blood becomes polluted with toxic levels of acidic ketones. Severe dehydration occurs rapidly because the kidneys are unable to conserve water in the presence of such extraordinary levels of blood glucose. This dangerous state is referred to as diabetic ketoacidosis, and it must be treated as a medical emergency, usually necessitating intravenous

CHAPTER 165 

BOX 165.3  Optimal Range for Self-

Monitored Blood Glucose

• Fasting or before meals: 80 to 110 mg/dL (4.4–6.7 mmol/L) • 2 hours after eating (postprandial): 2000 g

Morlans

n.a.

Ibanez

>217 g

Elseviers

>1000 pills

Kurth

>7000 pills 0.1

ANALGESIC INGREDIENTS

Sandler Pommer Morlans Perneger

2.69

1.6

2.89

1.8

0.8

1.1 1.02

2.1

17.2

8.5

34.7

4.2 4.6 4.7 4.2

1.3

n.a.

Dubach

2.79

1.9

>500 DDD

van der Woude

B

8.10

2.8 6.10

1.4 1.26

23.1 25.9

2.2

0.7 1

10

100

10

100

ASPIRIN

Fored Ibanez van der Woude Kurth Curham

Sandler Pommer Morlans Perneger

PARACETAMOL

Fored Ibanez van der Woude Kurth Curham Sandler Perneger Ibanez van der Woude Kurth Curham

C

4494 healthy male physicians, aged 40-84, followed for 15 years, outcome decreased eGFR

NSAIDs

0.1

1 Odd’s Ratio (95% CI)

Fig. 190.3  Risk of kidney failure from long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). (From Wei L, MacDonald TM, Jennings C, et al. Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function. Kidney Int. 2013 Jul;84[1]:174–178.)

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is commonly seen with celiac disease, chronic liver disease, dermatitis herpetiformis, psoriasis, ankylosing spondylitis, inflammatory bowel disease, IgA monoclonal gammopathies, HIV infection, certain cancers, and mycosis fungoides. Although the disease is found in all age groups, children and young adults are more commonly affected, with a higher ratio of males to females. Most commonly, the person will present with macroscopic hematuria along with an upper respiratory tract infection. The person is usually asymptomatic but may present with fatigue, malaise, or muscle soreness or pain. Children and some adults may complain of loin pain. A distinction from post-streptococcal nephritis (PSN) can be made because the symptoms usually occur 10 to 14 days after infection, and the patient may have had a fever before the onset. Additionally, hypertension and peripheral edema, commonly seen with PSN, are usually not seen with IgA nephropathy. Hematuria may last hours to days and may become intermittent with periods of no bleeding and then recur several months or years later after a febrile illness. Occasionally the hematuria is also accompanied by proteinuria of varying degrees, usually less than 1 g/day. Henoch–Schönlein purpura, which is found more often in children, may also have associated arthralgia with a lack of joint swelling and inflammation; a skin rash primarily over the legs and lower trunk that rapidly becomes purpuric; and severe abdominal pain, ileus, and bloody diarrhea. Less commonly, the presentation will be a nephrotic syndrome with renal insufficiency and hypertension. 

Acute Post-Streptococcal and Postinfectious Nephropathy Acute post-streptococcal and post-infectious glomerulonephritis are a result of the deposition of circulating immune complexes in the glomerulus. This is often due to the presence of group A beta hemolytic streptococcus (BHS) after pharyngitis or a skin infection (cellulitis, impetigo). Other microorganisms, such as bacteria, viruses, and parasites, have been implicated as well. Post-streptococcal glomerulonephritis (PSGN) is the most commonly encountered form of glomerulonephritis in children, with subclinical asymptomatic cases occurring 4 times more frequently than acute disease. There is some association with disease development in families, which may also be due to blood type and the presence of certain human leukocyte antigens (HLAs).19,20 There appears to be a 2:1 male-to-female ratio even though susceptibility to BHS infection is not sex related. The onset of the disease is usually abrupt and follows an infection with group A BHS. There is a latent period of 7 to 21 days after the infection before symptoms, such as edema and hematuria, occur. Periorbital edema is commonly observed. Hypertension may be present, resulting in headaches, visual disturbances, and altered sensorial states. Coma and convulsions may occur in severe cases. Circulatory congestion due to fluid retention results in dyspnea, cough, orthopnea, and cardiac and pulmonary changes suggesting pulmonary edema and congestive heart failure. PSGN should always be considered in patients presenting with cardiovascular or upper respiratory diseases of rapid onset. Diagnosis is made by urinalysis positive for hematuria and RBC casts. However, white blood cell (WBC), tubular epithelial, and granular casts are also commonly found and reflect the degree of pathology present. Serum creatinine levels tend to remain stable, but blood urea nitrogen (BUN) levels may rise somewhat. Changes in electrolyte balance will parallel changes in metabolic acidosis or alkalosis and need to be monitored frequently. Anti-streptolysin O (ASO) titers begin to rise about 10 to 14 days post–streptococcal pharyngitis, peak at about 4 weeks, and return to normal levels between 1 and 6 months later.

The magnitude of the titer does not seem to correlate to the degree of kidney involvement. Depression of hemolytic complement activity (C3) is present almost 100% of the time but also does not correlate to the degree of kidney involvement. 

Rapidly Progressive Glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) is defined as an idiopathic primary glomerular disease characterized by a rapidly progressing deterioration in renal function over a period of days to weeks to a few months. The definition is somewhat complicated because a rapid deterioration of kidney function can occur with a variety of illnesses. The cause of illness must be ruled out before a diagnosis of RPGN can be obtained. If untreated, the condition will commonly progress to end-stage kidney failure or death. Diagnosis is by kidney biopsy confirming renal failure to be related to circulating antiglomerular basement membrane antibodies. A relationship to primary alveolar disease, such as Goodpasture’s disease, has been suggested but not proven. The disease can be divided into three types, suggesting a vasculitis type of disease, circulating immune complexes as a pathogenesis, and possibly a relationship to HLA antigens and specific disease activity.40,41 

Nephrotic Syndrome Nephrotic syndrome (NS) is a recognized condition that can be the result of several diseases and is not considered a disease itself but rather a collection of symptoms due to kidney failure. Nephrotic syndrome is characterized by very high levels of urinary protein, low levels of serum total protein, swelling of the extremities (especially around the eyes), and high serum cholesterol. Nephrotic syndrome can be caused by diseases that affect the glomerular filtration of the kidneys, such as focal segmental glomerulosclerosis (FSGS) or membranous nephropathy and are termed primary NS. Systemic diseases such as diabetes or lupus (secondary NS) can also cause nephrotic syndrome. Most cases of nephrotic syndrome in adults have secondary causes, with diabetes being the most common.42,43 

DIAGNOSIS OF CHRONIC KIDNEY DISEASE As previously mentioned, many patients with CKD have no knowledge of its presence until it is at somewhat of an advanced stage. This is because of the body’s substantial organ reserve and ability to adapt to chronic conditions, or the person believes that it is due to another disease or part of the aging process. Signs and symptoms may be minimal at first, and the patient may complain of feeling run-down or fatigued. The skin may become ruddy, dry, itchy, and perhaps yellowish in color. Mental processes and movements may become slower, and as the disease advances, the person may become anorexic and have cramping, numbness, and tingling of the extremities and may complain of insomnia. At a minimum, a fasting chemistry screen and lipid levels should be ordered and include BUN, creatinine, and uric acid levels to assess kidney filtration. A complete blood count (CBC) to determine whether there is anemia, along with a fasting glucose, hemoglobin A1c, and insulin level to rule out metabolic syndrome or diabetes, and inflammatory markers such as serum ferritin, high-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) should also be considered. Additionally, a routine urinalysis with microscopical examination should be performed, and if albumin is present, then a total protein/ creatinine ratio is required to assess protein loss. A 24-hour urine creatinine clearance can follow this to establish a baseline to evaluate patient response to therapy.44

CHAPTER 190  Several parameters, if noted early on, suggest developing kidney disease. One of the earliest manifestations is the development of microalbuminuria with a normal (calculated) GFR.45 A change in the slope of serum creatinine levels over time is a predictor of decreasing kidney function, with a greater slope correlating with a greater decrease in function. The association of low serum albumin corresponding with a faster rate of GFR decline was more consistently noted in studies of diabetic patients than nondiabetic patients. The effect that dyslipidemia has on kidney decline is based on high levels of total cholesterol, triglycerides, or low-density lipoprotein and low levels of high-density lipoprotein. Several studies looking at individual or the totality of these parameters showed varying results, suggesting that there may be some association. Smoking seems to have an effect on changes in GFR, with smokers being found to have a greater rate of deterioration.45 The GFR can be estimated from serum creatinine levels by using prediction equations that also account for age, sex, race, and body size. Two such equations are the Cockcroft–Gault and the Abbreviated MDRD study equations. The MDRD equation has largely replaced the Cockcroft–Gault equation because it is believed to be more accurate and precise for persons with a GFR of less than approximately 90 mL/min per 1.73 m2 and does not require height and weight. Thus it is easily calculated and can be included with routine laboratory panels. Cr )

{

/ (72×S

{

CCr = ((140 − age) × weight)

× 0.85 (if female):

(The Cockcroft and Gault formula (1973)) ∘

∘

eGFR = 175 × (SCr )-10154 × (age)- 0. 203 × 0.742 [if female] × 1.212 [if Black]: (MDRD equation) CCr∘( creatinine clearance) = mL/minute Age = years Weight = kg SCr (serum creatinine) = mg/dL

Although both equations are good for screening for potential kidney disease development, there is some question as to the validity of the MDRD equation in diabetic kidney disease, in patients with serious comorbid conditions, in “normal” patients, or in patients older than 70 years of age. In these cases, the Cockcroft–Gault equation may provide a better assessment. The value of using both equations is in individuals with extremes of age and body size, severe malnutrition or obesity, diseases of skeletal muscle, paraplegia or quadriplegia, vegetarian diet, or rapidly changing kidney function. They can also be used to determine the dose of potentially toxic drugs that are excreted by the kidneys. Other screening parameters of note are the serum calcium/phosphorus ratio and calcium X phosphorus, which is an assessment of the kidney’s ability to balance calcium and phosphorus as well as to assess parathyroid function, response to vitamin D, and renal calcinosis. As serum calcium levels fall, there is a rise in phosphorus, resulting in symptoms of hypocalcemia. However, changes noted

Kidney Disease

1513

over time on routing chemistry screens may provide a clue for developing kidney disease. The normal calcium/phosphorus ratio = (2.5 ± 0.4), and the normal calcium X phosphorus = (N = < 40 and abnormal = 60 or >). 

STAGES OF CHRONIC KIDNEY DISEASE Kidney disease is recognized as a chronic, progressive disease and is classified according to the following stages: Stage 1—Signs of mild kidney disease but with normal or better GFR (greater than 90% kidney function) Stage 2—Signs of mild kidney disease with reduced GFR (indicating 60%–89% kidney function). Stage 3—Signs of moderate chronic renal insufficiency (where the GFR indicates 40%–59% kidney function) Stage 4—Signs of severe chronic renal insufficiency (where the GFR indicates 15%–29% kidney function). Stage 5—Signs of end-stage renal failure (where the GFR indicates less than 15% kidney function). 

THERAPEUTIC APPROACH Case Management Considering the many different causes of chronic kidney disease, comorbid disease management is as important as the management of the kidney disease itself. This has been one of the challenges facing physicians as medicine has become more compartmentalized, with specialists treating isolated organ systems. Polypharmacy is increasingly recognized as contributing to morbidity, negative health outcomes, and decreasing the quality of life.46 Polypharmacy is particularly relevant to kidney function because many of these drugs, such as antihypertensive medications, directly affect kidney function. In children affected with any type of kidney disease, it is important to consider that the kidney is still maturing. This may present a dilemma. In prolonged cases, severe damage can take place, altering kidney-centered parameters and affecting growth and development, as well as predisposing the person to an earlier development of kidney failure. However, in a disease state of shorter duration, a developing kidney has a greater chance of complete recovery if recognized and treated early. A treatment regimen that considers the type of kidney disease, precipitating etiology, duration, and expected changes in the pathophysiology of the disease must be developed. This may consist of dietary modifications, allergen identification, and control of hypertension and diabetes if present. The goal of treatment is to relieve the perturbing insult on the kidney and allow healing and restoration of normal function to occur. Therefore periodic follow-up visits are needed once the initial insult has been eliminated or has reached equilibrium. Education of the patient as to the possible course of the disease, the patient’s susceptibility to it, and the significance of prevention to maintain the disease or the recovered level of health is important. A periodic routine urinalysis is beneficial for screening, especially after any febrile or respiratory illness. 

Dialysis Patients on renal dialysis present additional challenges for the clinician because each requires different levels of monitoring and follow-up. Hemodialysis is commonly performed 3 times per week, requiring the patient to be connected to a dialyzer that cleans the blood. This procedure takes between 3 and 5 hours and requires frequent blood testing to monitor electrolyte and protein balance. Peritoneal dialysis,

1514

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Diseases

on the other hand, is carried out at home by the patient and is achieved through continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). From a holistic perspective, it is much easier for the clinician to treat patients on CAPD and CCPD than hemodialysis simply because the mechanism of dialysis CAPD and CCPD works with the body’s alternative filtering mechanism, the omentum, to achieve dialysis rather than filtering the blood, which necessitates a rebalancing of blood chemistry. However, both methods increase the likelihood of sepsis due to contamination of fluids. Therapies to prevent sepsis seem to work better with CAPD and CCPD than hemodialysis. Additionally, the balancing of blood chemistry and working with the patient’s dietary requirements are also easier to address.47 

NUTRITIONAL CONSIDERATIONS IN ACUTE AND CHRONIC RENAL FAILURE The goals of nutritional therapy in ESRD are to maintain the body’s chemical composition as close to that of normal to preserve protein stores until renal function is normalized. Nutritional therapy in acute renal failure (ARF) is complicated because of the rapid and fluctuating progression of the disease, in contrast to ESRD, which is slower and more predictable. Diets with high-quality protein and high carbohydrate (2200 calories) intake, with an excess of 500 mL of water above the daily output, are desired. Intake of water, electrolytes, and minerals must be closely monitored, especially in patients undergoing dialysis, to avoid fluid overload while minimizing abnormal concentrations of these substances. Protein restriction must occur to decrease the accumulation of nitrogenous wastes as well as other inorganic ions, such as sulfates and phosphates, which result from protein metabolism. A sufficient intake of calories and vitamins is needed to minimize catabolism of protein stores. High-carbohydrate diets in patients with renal failure were found to reduce endogenous protein catabolism, decreasing the BUN.

Water and Mineral Balance Patients with ARF often show greater impairment of water, mineral, and electrolyte excretion than do patients with ESRD, even though the creatinine clearances may be similar. This is due to an inability of the body to adjust to the rapid changes occurring with ARF as opposed to the slower rate of change with ESRD. Water intake may need to be negative to balance the serum ion concentration. Water loss must account for the patient’s temperature, any surface loss through burns or open wounds, the rate of ventilation, and the humidity of the air. In afebrile patients without burns, fluid losses of 400 to 600 mL/day are seen. Water loss can be monitored by measuring weight changes and the differences between fluid intake and output, as well as calculation from body composition analysis. Edema and hypernatremia indicate an excess of salt and water, whereas postural hypotension suggests volume loss. In patients with edema, hypernatremia requires water and salt restriction until the serum sodium concentration is normalized and the edema is reduced. In patients with postural hypotension, careful use of salt and/or blood or colloid is needed to correct the volume deficit. Hyperkalemia usually requires dialysis to remove potassium because it is primarily due to renal impairment. 

Dietary Protein Requirements Patients with ESRD are in neutral or positive nitrogen balance with ingestion of 40 g/day of high-quality protein but can go into negative

balance with only 20 g/day. It has been shown that 0.5 to 0.8 gm/kg/ day of protein is needed to maintain a neutral nitrogen balance and that higher amounts are needed with patients on dialysis. Patients on hemodialysis need higher protein amounts due to loss from the procedure. This also includes peritoneal dialysis. One g/kg/day is needed, and if the person is restricted to less, he or she will go into negative nitrogen balance. Essential amino acids (AAs) need to be part of the regimen because a person lacking only one of the essentials AAs will develop a negative nitrogen balance as the rate of protein synthesis decreases in the absence of the amino acid. Branched-chain AAs have been shown to increase muscle protein synthesis while decreasing muscle degradation. Branched-chain AAs, which include leucine, isoleucine, and valine, showed a decline in degradation, especially leucine, which, by itself, can decrease catabolism. Protein-sparing effects were noted not only during the administration of the amino acid solution but up to a week after administration. 

General Principles of Nutrient Administration 1. Adequate calories and nitrogen should be administered with a minimal amount of water. 2. High-quality protein should be administered in sufficient amounts to achieve neutral nitrogen balance but not so high as to increase urea nitrogen levels. 3. Sodium intake should be adjusted to achieve sodium output unless edema is present. If edema is present, then sodium should be restricted to a quantity less than the daily excretion. Potassium, calcium, magnesium, and phosphate should be monitored to make sure adequate serum concentrations are maintained. 4. Patients should be encouraged to eat, and the minimal dietary requirements for renal insufficiency should be followed unless there is a catabolic illness requiring a greater intake of protein. 

Nutritional Therapies for Chronic Kidney Disease There are a considerable number of natural therapies that can be used for patients with CKD, not only to support kidney function and decrease rates of decline but also to support the other emunctories that must compensate for decreased kidney function. Therefore liver and skin support for detoxification and elimination are important to address as part of a comprehensive CKD program. As with all natural therapies, individualization of treatment plans is important because patients with CKD will present with their own unique presentations due to the stressors of the disease process. Most of the causes of kidney damage can be controlled by helping people make better choices. The key environmental nephrotoxic agents include cadmium, mercury, fluorinated hydrocarbons, and glyphosate. Decreasing exposure is primarily accomplished by modifying lifestyle choices. This includes eliminating or significantly reducing consumption of conventionally grown foods (e.g., soybeans), eliminating tobacco smoking, avoiding genetically modified organism (GMO) foods, eliminating or reducing consumption of large fish (e.g., tuna), avoiding nonstick coatings on pots and pans, and avoiding clothing that is waterproof but breathable. Some of the most immediate benefits can be seen by decreasing toxins of choice, such as excessive dietary salt, excessive dietary phosphates, and drugs such as NSAIDs. Organic, mostly plantbased foods should be consumed when possible. Eating organic foods has been shown to measurably decrease POP levels within 3 days.48

Vitamin C Vitamin C supplementation in patients with CKD, especially those on dialysis, has been reviewed in several studies looking at its antioxidant effects for lipid peroxidation, enhancement of cellular function, and

CHAPTER 190 

Kidney Disease

1515

its role in mobilizing iron to form hemoglobin. Because there is a high turnover of RBCs in patients with CKD, iron stores will increase due to chronic inflammation and loss from dialysis. Vitamin C plays a key role in mobilizing iron for hemoglobin formation. However, in CKD, an increase in oxidation may occur because of ascorbate, causing additional stress to already-uremic patients. Depending on the study, levels of 60 to 300 mg per day or 1 to 1½ g per week are recommended above intake from food sources.49,50 

well as a mucolytic in patients with cystic fibrosis and chronic obstructive pulmonary disease. NAC also provides protection in patients with CKD by increasing glutathione production and reducing exposure to acetaminophen and contrast dyes.62,63 Additionally, NAC has been shown, along with the iron chelator deferoxamine and Ginkgo biloba extract, to protect against cisplatin lipid peroxidation, with NAC and deferoxamine having the greatest effect.64 

Vitamin D

Alpha-lipoic acid (ALP) has been shown to attenuate the effects of other antioxidants, such as vitamins C and E, especially in patients with diabetic nephropathy. Additionally, ALP increased renal cortical glutathione levels in patients with diabetes.65 Another study looked at the effects of ALP on doxorubicin-induced renal damage and found that there was greater mitigation of oxidative stress, inflammation, and apoptosis parameters with pretreatment with ALP. These studies suggest that ALP, used in conjunction with other antioxidants, provides additional protection against oxidative stress in CKD.66 

Patients with CKD show reduced levels of 1-α hydroxylase, the enzyme that converts calcifediol/25-hydroxyvitamin D (25[OH]D) to its more active form, calcitriol/1,25-dihydroxyvitamin D (1,25[OH]2D). Because of this, patients with CKD are most often supplemented with a vitamin D replacement of the active form of 1,25-dihydroxvitamin D.51 Because extra-renal 1-α hydroxylation does occur, some nephrologists recommend supplementing with the unactivated form of vitamin D, allowing the extra-renal sites to regulate calcium and phosphorus balance.52 The half-life of calcifediol/25-hydroxyvitamin D (25[OH]D) is 2 to 3 weeks except in renal failure, where it will last up to 2 to 3 times that. The half-life of calcitriol/1,25-dihydroxyvitamin D (1,25[OH]2D is 3 to 6 hours, but the pharmacological activity can last 3 to 6 days. When administering vitamin D, the serum calcium and phosphorus levels should be checked monthly to adjust dietary intake because of changes in kidney production as well as supplementation. In dialysis patients, they should be checked weekly.51,53 

Alpha-Lipoic Acid

Carnitine Carnitine supplementation slows the rate of kidney function loss while improving skeletal and cardiac muscle function as well as decreasing anemia, all found in CKD patients. Carnitine slows the rate of kidney function loss, and its deficiency is a common occurrence in dialysis patients, where supplementation has been shown to decrease hospital use in this group.67,68 

Vitamin E

Curcumin

Vitamin E has been shown to be an excellent protector and stabilizer of cell membranes, especially in RBCs and lung tissue. This is because of its antioxidant properties, anti-inflammatory, and anti–platelet aggregation effects. Vitamin E was shown in one study to lower the protein/creatinine ratios while somewhat increasing the mean GFR.54,55 Asymmetrical dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, is elevated in CKD and is considered a risk factor for the development of arteriosclerosis. A study evaluating the effects of ADMA concluded that vitamin E supplementation increased the bioavailability of nitric oxide, lowering the risk of arteriosclerosis.56 

Curcuma longa is a potent antioxidant that protects against protein loss, albuminuria, and hyperlipidemia as well as decreasing kidney damage due to free-radical formation. Additionally, it was found to increase glutathione and glutathione peroxidase activity while eliminating kidney microsomal and mitochondrial lipid peroxidation.69,70 

Fish Oil Consumption of fish, either in the diet or supplemented fish oils, shows a reduction in the development of CKD.57 Fish oil supports kidney function through anti-inflammatory effects and the regulation of blood pressure.55 Fish oil has also been found to slow the progress of kidney disease in patients with IgA nephropathy. Fish oils have also been found to protect renal function in patients undergoing Cyclosporin therapy for psoriasis as well as with renal transplant.58,59 

Flax Oil Flax oil, a source of alpha-linoleic acid, has been found to be beneficial because it reduces renal injury in experimental polycystic kidney disease by decreasing associated interstitial nephritis.60 This is due in large part to its anti-inflammatory properties and its ability to alter the renal content of polyunsaturated fatty acids, which promotes the formation of less inflammatory classes of renal prostanoids.61 

N-Acetylcysteine N-Acetylcysteine (NAC) is believed to promote the production of glutathione, an antioxidant that prevents damage to important cellular components caused by free radicals, lipid peroxidation, and heavy metals. NAC is used for the treatment of acetaminophen toxicity as

Glandulars Dietary use of renal protomorphogen (kidney tissue extract) helps decrease circulating immune-complex damage in autoimmune disease as well as provide nutrients and growth factors for renal regeneration. Many cultures use organ-specific nutrients when treating specific disease conditions like CKD, as well as to support normal growth and development. 

Homeopathy Homeopathic prescriptions for patients with CKD have, in many cases, slowed, stopped, or reversed the progress of the disease. This is particularly seen in patients with acute kidney failure whose course is often rapid and severe, requiring lesional, fundamental, and constitutional prescriptions. In patients with CKD, prescriptions are more often constitutional or miasmic due to the slowly evolving nature of the disease. Often used in conjunction with other natural therapies, a wide variety of homeopathic medicines are used to direct the healing process or with dialysis patients to reduce the risk of sepsis and toxemia.71 

Botanical Medicines Botanical medicines, such as Aconite napellis, Arctostaphylos uva ursi, Atropa belladonna, Eupatorium purpureum, Juniperus officinalis, Galium aparine, Rheum palmatum, Salviae militorrhizae, and Solidago odora, are commonly used for CKD. Botanical medicines work differently than drugs in that they contain several different constituents that affect a variety of parameters of kidney function.72–74

1516

SECTION 6 

Diseases Effect of BB on renal hemodynamic dysfunctions in a LPS-induced AKI model Glomerular Filtration Rate (GFR) Mean Arterial Pressure (MAP)

100

50

SAL

1.5 1.0 0.5

BB

SAL

Control

BB

SAL

VIPER

LPS

***

**

15 10 5 0 SAL

BB

SAL

Control

BB

SAL

BB

VIPER

LPS

Renal Vascular Resistance (RVR) mmHg/ml/min/g kidney wt

ml/min/g kidney wt

20

BB

Control

B

Renal Blood Flow (RBF)

C

***

0.0

0

A

***

2.0 ml/min/g kidney wt

mm Hg

150

VIPER

LPS

***

25

***

20 15 10 5 0 SAL

D

BB

SAL

Control

BB

VIPER

LPS

Fig. 190.4  Blueberries protect the kidneys from gut-derived toxins.

Salvia Militorrhizae As an example, Salvia militorrhizae increases blood flow to the kidney by decreasing platelet adhesion, enhances urea and creatinine clearance, stabilizes the glomerular basement membrane by enhancing electrical charge, provides antioxidant and free-radical neutralization, and decreases lipid peroxidation due to the presence of magnesium lithospermate B. It also affects blood pressure by enhancing prostaglandin E2 for vasodilation while limiting the effects of thromboxane A2 that contribute to vasoconstriction.75 

Hydrastis, Phytolacca, Bryonia, and Baptisia Herbal medicines such as Echinacea, Hydrastis, Phytolacca, Bryonia, and Baptisia, when used in combination, reduce the risk of the development of sepsis in dialysis patients. The combination is taken prophylactically and at an increased dosage at the first signs of developing sepsis. The formula is often used in conjunction with homeopathic Pyrogenum and/or Echinacea and has been found to quickly restore normal homeostasis.76 

Gotu kola Traditional Chinese medicine has used Gotu kola to treat kidney diseases for centuries. Asiaticoside has been shown to improve microcirculation and reverse fibrosis in humans with varicose veins. Its direct benefits for the kidneys have only been shown in animals but are encouraging. In rats, G. kola showed a protective effect for Adriamycininduced nephropathy, resulting in dramatically improved kidney

function.77 Another study combined G. kola in conjunction with naringenin and showed decreased fibrosis formation in the kidneys.78 

Dark Chocolate Dark chocolate consumption improves oxygenation of the kidneys in all individuals. The benefit is directly proportional to catechin levels.79 Animal research has shown that catechins also protect the kidneys from oxidative stress from toxic drugs like cyclosporine.80 

Blueberry Blueberry anthocyanins specifically protect the kidneys from bowel-derived endotoxins. Fig. 190.4 shows how blueberries increase the GFR in normal kidneys (but the increase is not statistically significant) and completely protect the kidneys from the dramatic lowering of GFR caused by gut toxins in those with impaired function.81 

Zingiber officinale There is ample animal research showing that Zingiber officinale not only improves kidney function but is especially beneficial in protecting the kidney from cadmium. The primary mechanism of protection appears to be ginger’s ability to decrease inflammation and oxidative damage to kidney tissue exposed to a variety of toxins. The anti-­inflammatory benefits of ginger in the kidney result from its antioxidant properties and the epigenetic downregulation of proinflammatory genes.82 Several animal studies have shown that ginger can protect the kidneys from cadmium. One study found the anti-inflammatory effects

CHAPTER 190 

Kidney Disease

Effect of administration of polyphenols from ginger on kidney function parameters of normal and streptozotocin-diabetic rats. Group

Kidney function test Urea (mg/dL)

Control Diabetic untreated Diabetic + Free Diabetic + Bound Diabetic + Glibenclamide

1.99a

14.82 ± 50.61 ± 6.82b 22.63 ± 2.09c 27.05 ± 2.12c 35.82 ± 3.87c

Creatinine (mg/dL) 1.72 ± 0.26a 2.52 ± 0.53a 2.01 ± 0.29a 2.83 ± 0.71a 2.11 ± 0.23a

Values are mean ± S.E.M. of 8 rats per group. Test values down the vertical columns carrying different superscripts are significantly different (p < 0.05). Fig. 190.5  Ginger partially restores kidney function in diabetic rats.

of ginger to be strong enough to prevent most of the kidney damage from cadmium.83 Another found almost no histological kidney damage when ginger was fed along with cadmium.84 Animal research has also shown kidney protection from alcohol, malathion, carbon tetrachloride, chromates, fructose, gentamycin, ischemia, lead, and cancer drugs.85–87 Fig. 190.5 shows restoration of kidney function in rats that already had diabetes.87 Herbal medicines have also been found to contribute to the development of CKD when used incorrectly, misidentified, or contaminated. Consulting a botanical material medica before prescribing for CKD is highly recommended.88 

THERAPEUTIC APPROACH There is no substitute for vigorously avoiding all causes of kidney damage, especially environmental toxins and NSAIDs.

Supplements Vitamin C: 500 mg/d Vitamin E: 1000 IU mixed tocopherols/d Fish oil: 3 g/d NAC: 500 mg/d 

Botanical Medicines G. kola extract: 30 to 90 mg/d Dark chocolate: to tolerance Blueberry extract: 1000 mg/d

REFERENCES See www.expertconsult.com for a complete list of references.

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68. M1 C, Benatti P, Mancinelli A, et al. Carnitine replacement in end-stage renal disease and hemodialysis. Ann N Y Acad Sci. 2004;1033:52–66. 69. Narayanan V, Punithavathi D, Arumugam V. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol. 2000;129(2):231–234. PMC. Web. Nov 15. 2017. 70. Ghosh SS, Gehr TWB, Ghosh S. Curcumin and chronic kidney disease (CKD): major Mode of action through stimulating endogenous Intestinal alkaline Phosphatase. Molecules. 2014;19:20139–20156. 71. Boericke W. Materia Medica with Repertory. 9th ed. Philadelphia, PA: Boericke & Runyon; 1927. 72. Felter-Lloyd. King’s American Dispensatroy. Sandy, Oregon. Eclectic Medical Publications; 1997. 73. Felter H. The Eclectic Materia Medica, Pharmacology and Therapeutics. Portland, Oregon: Eclectic Medical Publications; 1983. 74. Ellingwood F. American Materia Medica, Therapeutics and Pharmacognosy. Portland, Oregon: Eclectic Medical Publications; 1983. 75. Wu XJ, Wang YP, Wang W, Sun WK, Xu YM, Xuan LJ. Free radical scavenging and inhibition of lipid peroxidation by magnesium lithospermate B. Acta Pharmacol Sinica. 2000;21(9):855–858. 76. Scudder J. Specific Diagnosis A Study of Disease. Portland, OR: Eclectic Medical Publications; 1983. 77. Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cytoskeletal proteins and renal slit diaphragm proteins in adriamycin-induced rat nephropathy. Life Sci. 2013;93(8):352–358. 78. Meng XM, Zhang Y, Huang XR, et al. Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015. https://doi.org/10.18632/oncotarget.6100. [Epub ahead of print]. 79. Pruijm M, Hofmann L, Charollais-Thoenig J, et al. Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers. Clin Nephrol. 2013;80(3):211–217. 80. Al-Malki AL, Moselhy SS. The protective effect of epicatechin against oxidative stress and nephrotoxicity in rats induced by cyclosporine. Hum Exp Toxicol. 2011;30(2):145–151. 81. Nair AR, Masson GS, Ebenezer PJ, et al. Role of TLR4 in lipopolysaccharide-induced acute kidney injury: protection by blueberry. Free Radic Biol Med. 2014;71:16–25. 82. Kim MK, Chung SW, Kim DH, et al. Modulation of age-related NFkappaB activation by dietary zingerone via MAPK pathway. Exp Gerontol. 2010;45(6):419–426. 83. Onwuka FC, Erhabor O, Eteng MU, Umoh IB. Protective effects of ginger toward cadmium-induced testes and kidney lipid peroxidation and hematological impairment in albino rats. J Med Food. 2011;14(7–8):817–821. 84. Baiomy AA, Mansour AA. Genetic and histopathological responses to cadmium toxicity in Rabbit’s kidney and liver: protection by ginger (Zingiber officinale). Biol Trace Elem Res. 2015. [Epub ahead of print]. 85. Shanmugam KR, Ramakrishna CH, Mallikarjuna K, Reddy KS. Protective effect of ginger against alcohol-induced renal damage and antioxidant enzymes in male albino rats. Indian J Exp Biol. 2010;48(2):143–149. 86. Baiomy AA, Attia HF, Soliman MM, Makrum O. Protective effect of ginger and zinc chloride mixture on the liver and kidney alterations induced by malathion toxicity. Int J Immunopathol Pharmacol. 2015;28(1):122–128. 87. Kazeem MI, Akanji MA, Yakubu MT. Amelioration of pancreatic and renal derangements in streptozotocin-induced diabetic rats by polyphenol extracts of Ginger (Zingiber officinale) rhizome. Pathophysiology. 2015; pii: S09284680(15)30009-2. https://doi.org/10.1016/j.pathophys.2015.08.004. [Epub ahead of print]. 88. JHA V. Herbal medicines and chronic kidney disease. Nephrology. 2010;15:10–17. https://doi.org/10.1111/j.1440-1797.2010.01305.

191 Kidney Stones Geovanni Espinosa, ND, LAc, IFMCP, CNS, and Ralph Esposito, ND, LAc OUTLINE Diagnostic Summary, 1518 General Considerations, 1518 Diagnostic Considerations, 1519 Stone Formation, 1519 Therapeutic Considerations, 1519 Stone Composition, 1519 Diet, 1521 Sodium and Salt, 1521 Fructose, 1522 Dietary Recommendations for Patients With High Urine Oxalate, 1522 Gut Flora, 1522

Nutrients, 1522 Botanical Medicines, 1525 Lifestyle, 1526 Miscellaneous, 1526 Therapeutic Approach, 1526 Acute Obstruction, 1527 Calcium Stones, 1527 Uric Acid Stones, 1527 Magnesium–Ammonium–Phosphate Stones, 1527 Cystine Stones, 1527 Brushite and Struvite Stones, 1527

DIAGNOSTIC SUMMARY

hypercalciuria. Other identified genetic changes are being linked to excess urinary excretions of oxalate, cystine, and uric acid.3 A recent systematic review found that 20 genes and more than 42 single-nucleotide polymorphisms (SNPs) may relate to stone matrix, calcium and phosphate regulation, inflammation, and oxidative stress, all of which contribute to stone formation. The complexities of genomics are not yet completely solidified; thus suggesting that the cause of stones is primarily related to an SNP is premature. However, this still provides us with a deeper insight as further research emerges.4 The incidence of renal stones varies geographically, reflecting differences in environmental factors, diet, and components of drinking water. Human urine is supersaturated with respect to calcium oxalate, uric acid, and phosphates. These substances normally remain in solution because of pH control and the secretion of inhibitors of crystal growth. The following primary and secondary metabolic diseases cause kidney stones and must be ruled out early in the clinical process: • Hyperparathyroidism • Cystinuria • Vitamin D excess • Milk-alkali syndrome • Destructive bone disease • Primary oxaluria • Cushing syndrome • Sarcoidosis • Acid-forming diet Evolving research is showing that acid-forming diets (i.e., diets whose constituents require a metabolic response to neutralize and increase excretion of acids) appear to underlie many of the dietary factors—especially salt and foods with sulfur-containing amino acids— and have been shown to play a key role in the formation of both calcium and urate stones. This finding also helps explain the protective effects of a diet high in fruits and vegetables. 

• U  sually asymptomatic • Diagnosed adventitiously or from acute symptoms if urinary tract obstruction • Excruciating, intermittent, radiating pain to the groin area originating in the flank or kidney • Nausea, vomiting, and abdominal distention • Chills, fever, and urinary frequency if infection present 

GENERAL CONSIDERATIONS Stone formation in the urinary tract has been recognized for thousands of years; during the past few decades, however, both the pattern and incidence of the disease have changed markedly. In the past, stone formation occurred almost exclusively in the bladder, but today most stones form in the upper urinary tract (Fig. 191.1). Males have a 3:1 ratio in the formation of kidney stones compared with females except in the sixth decade, where the incidence falls in men but rises in women—a trend toward gender equivalence.1 Once a kidney stone does form, there is a 50% chance of recurrence within 5 to 7 years if there is no treatment. Kidney stones are not limited to any cultural, geographical, or racial groups. In the United States, 1 of every 11 Americans is affected by kidney stones, with the emergency department (ED) being the most common resource for patients. Of these, 11% return within the first 30 days after an ED visit.2 The incidence has been steadily growing, paralleling the rise in other diseases associated with the so-called Western diet—ischemic heart disease, cholelithiasis, hypertension, and diabetes. In the western hemisphere, over 80% of kidney stones are usually composed of calcium salts, uric acid (5%–8%), or struvite (10%– 15%). Molecular research is beginning to link certain mutations in the genes responsible for handling renal chloride, which can lead to

1518

CHAPTER 191 

Kidney Stones

1519

Human Kidney Stones Healthy Kidney

Kidney with Kidney Stones

cortical blood vessels interloblar blood vessels

minor calyx kidney stones

major calyx

renal artery renal vein

ureter

capsule

medula

Fig. 191.1  Kidney stone. (From https://www.istockphoto.com/vector/human-anatomy-diagram-with-kidneystones-gm922029526-253154531.)

Promotion factors Chemial driving force

Inhibition factors Urine supersarturation

Amorphous calcium phosphate

Citrate, HP, NC and UPTFI

Homogenous nucleation Heterogenous nucleation

Growth

Nucleation

Aggregation

Epitaxy growth Renal tubular cell injury

Crystal–cell interaction, fixation

Prevent cell injury

Secondary crystal growth, crystal aggregation Stone formation

Diet and medical therapy Gene therapy Protein modulation therapy

Fig. 191.2  Schematic diagram for the formation and inhibition mechanism of calcium-oxalate renal stone formation. (From Inhibition of urinary macromolecule heparin on aggregation of nano-COM and nano-COD crystals [Scientific Figure on ResearchGate]. https://www.researchgate.net/Schematic-diagram-for-theformation-and-inhibition-mechanism-of-calcium-oxalate-renal_fig1_271332535.)

DIAGNOSTIC CONSIDERATIONS Stone Formation Conditions favoring stone formation can be divided into two groups: factors increasing the concentration of stone crystalloids and factors favoring stone formation at normal urinary concentrations (Fig. 191.2). The first group includes a reduction in urine volume (dehydration) and an increased rate of excretion of stone constituents. The second group is related to urinary stasis, pH changes, foreign bodies, and reduction of normal substances that solubilize stone constituents. See Tables 191.1 and 191.2 for an outline of the diagnostic possibilities. 

THERAPEUTIC CONSIDERATIONS Stone Composition Diagnosing the type of kidney stone is critical to identifying the appropriate therapy. Careful evaluation of the following criteria usually

determines the composition of the stone if one is not available for chemical analysis: • Diet • Underlying metabolic or disease factors • Serum and urinary calcium, uric acid, creatinine, and electrolyte levels • Urinalysis • Urine culture Table 191.3 summarizes the findings in the major types of kidney stones.

Dietary Factors Calcium-containing stones are composed of calcium oxalate, calcium oxalate mixed with calcium phosphate, or very rarely calcium phosphate alone. The high incidence of calcium-containing stones in affluent societies is directly associated with the following dietary patterns: • Low amounts of fiber5 • Intake of highly refined carbohydrates6,7

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Diseases

TABLE 191.1  Causes of Excessive Excretion of Relatively Insoluble Urinary Constituents Constituent

Cause of Excess Excretion

Laboratory Findings

Calcium

(>250 mg/day excreted) Absorptive hypercalciuria Renal hypercalciuria (renal tubular acidosis) Primary hyperparathyroidism Hyperthyroidism High vitamin D intake Excess intake of milk and alkali Aluminum salt intake Destructive bone disease Sarcoidosis Prolonged immobility Methoxyflurane anesthesia

Low serum PO4 30%–40% of all stone formers High serum parathyroid hormone High urinary cyclic AMP High serum calcium High 1,25(OH)2D3 Low serum phosphate High 1,25(OH)2D3

Oxalate

Familial oxaluria Ileal disease, resection, or bypass Steatorrhea High oxalate intake Ethylene glycol poisoning Vitamin C excess (extremely unlikely)

Rare Vitamin B6 deficiency or abnormal oxalate metabolism

Uric acid

( 5.5

Small, hempseed- or mulberry-shaped, brown or black

Calcium oxalate + calcium phosphate Calcium phosphate

Apatite

6–8

Opaque

pH > 5.5

Staghorn configuration, light in color

Magnesium ammonium phosphate

Struvite triple phosphate

15–20

Opaque

pH > 6.2 Infection

Staghorn configuration, light in color

Uric acid

6–10

Translucent

pH < 6.0

Ellipsoid, tan or red-brown

Cystine

2–3

Opaque

pH < 7.2

Multiple, faceted, maple syrup color

Salt intake

Defect in excreting Na+

Ca2+ excretion

Retention of Na+ and H2O

Serum Ca2+

Compensatory hormonal response (PTH)

Hypertension

Kidney stones

Intestinal Ca2+ reabsorption

Bone Ca2+ resorption

Bone demineralization Osteoporosis

Fig. 191.3  Schematic representation of the effects of salt intake on calcium metabolism and its implications for kidney stone formation and bone health. (From Cappuccio FP. Cardiovascular and other effects of salt consumption. Kidney Int Suppl. 2013;3[4]: 312–315. PubMed PMID: 25019010. https://openi.nlm.nih.gov/ detailedresult.php?img=PMC4089690_kisup201365f1&req=4.)

DIET In one study, high levels of dietary calcium in men younger than age 60 were associated with decreased stone formation, but there was no effect in men older than age 60, nor was a supplemental dietary intake of more than 500 mg of calcium associated with an increased risk of stones.19 The specific type of stone was not elucidated in this study, and it was assumed that the majority of kidney stones reported by the cohort population consisted predominantly of calcium oxalate, as in the general population. The cause of this age-specific difference is unclear. Dietary calcium may bind to dietary oxalate in the intestine, thereby reducing oxalate absorption and the subsequent concentration of urinary oxalate. Both vitamin D deficiency and a diminished ability to absorb dietary calcium are more prevalent in older people.19

Sodium and Salt Regarding dietary salt content, observational studies suggested a strong relation between sodium consumption and hypercalciuria,

but more recent evidence has challenged this idea. High sodium intake is known to reduce renal tubular reabsorption of calcium, thereby increasing the amount of calcium excreted in the urine (Fig. 191.3).20 Also, a high-sodium diet is known to increase urine pH and has been proposed to reduce urine citrate.21 Other studies show a positive association between urinary sodium and calcium excretion and suggest that stone formers may be more sensitive to the calciuric effect of sodium.22 Nouvenne et al.23 found that when patients with idiopathic calcium stones were treated with sodium restriction (60 mmol/day) and high fluid intake, a reduction of 100 mmol of urinary sodium was accompanied by a reduction of 64 mg/day in urinary calcium, with 30% of patients achieving normal urine calcium. In contrast, other data, specifically in patients with hypocitraturia (not hypercalciuria), demonstrated that dietary sodium supplementation resulted in increased voided volume and decreased calcium-oxalate supersaturation.24 This must be carefully examined because these patients were followed for only a short period of time and were already using pharmacological interventions for stone

1522

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Diseases

disease. Although results continue to be conflicting, reduced dietary sodium is a general recommendation given to most patients with a history of kidney stones. 

Fructose Sports drinks have become increasingly popular within the past decade. The content of citrate in such beverages would be expected to increase urine citrate excretion and urine pH, providing protection against both calcium and uric acid stones. However, the purposely high sodium content of sports drinks, promoted as useful for “rehydration” in athletes, might be associated with increases in urine calcium excretion. In addition, the ingestion of significant amounts of sucrose and fructose in these drinks could also be associated with increases in calcium excretion.7 Fructose, a component of corn syrup frequently added to sports drinks and sodas as a sweetener, would also be an undesirable way for most stone formers to increase urine volume, given its recent links to hyperuricemia, metabolic syndrome, and stones.25,26 Citrate is an important inhibitor of the aggregation and growth of calcium-oxalate and calcium-phosphate crystals. In the past, dietary interventions to increase citrate have included lemonade and orange juice.27,28 The results with lemonade are conflicting, with one study showing an increase in urine volume but not in urine citrate.29 Another citrus juice, grapefruit, may prove to be effective in increasing urinary citrate levels and reducing the BONN risk index score, suggesting an overall protective effect on crystallization. Although the urinary oxalate levels may be increased, crystallization is decreased and offset by increased citrate.30–32 Regular consumption of grapefruit juice should be avoided, however. In one large-scale study, women drinking 8 oz of grapefruit juice daily increased their risk of stones by 44%. Hyperoxaluria is a metabolic risk factor for stone disease. Dietary oxalate may contribute as much as 80% of the urine oxalate.33,34 Therefore a low-oxalate diet may provide benefit for patients with hyperoxaluria. In addition, adequate dietary calcium to minimize intestinal oxalate absorption has been shown to be beneficial. Borghi et al.,35 in a randomized trial in men with recurrent calcium-oxalate stones, achieved a significant reduction in oxalate excretion and the incidence of recurrent stones for patients on a normal-calcium (1200 mg/day), low-animal-protein, low-salt diet compared with a low-calcium diet (400 mg/day). 

Dietary Recommendations for Patients With High Urine Oxalate Low-Oxalate Diet

A low-oxalate diet is a common prescription for recurrent calciumoxalate kidney stones. The ultimate goal is to reduce the level of oxalic acid being excreted in the urine. It appears that people with recurrent kidney stones have a tendency to absorb higher levels of dietary oxalates, up to 50%,33 compared with normal subjects not prone to kidney stones, who absorb only 3% to 8% of dietary oxalate. A low-oxalate diet is usually defined as less than 50 mg of oxalate per day, so foods in the high- and moderate-oxalate categories have to be curtailed. Box 191.1 provides an estimate of the oxalate content of food, which is highly variable. The level of oxalate in a particular food in published reports can vary twofold to fifteenfold. Differences in climate, soil quality, state of ripeness, or even which part of the plant is analyzed will also affect the value. Although the role of oxalates in the development and risk of kidney stones is unclear, with some research showing only a modest correlation, clinically it would be prudent for stone formers to reduce intake. However, the stringency of following a low-oxalate diet must

be considered and tailored to the patient and his or her potential comorbidities.36 

Weight and Carbohydrate Metabolism Weight control and the correction of carbohydrate metabolism are important because excess weight and insulin insensitivity lead to hypercalciuria and are high-risk factors for stone formation.37,38 After glucose ingestion, there is a rise in urinary calcium, and phosphate reabsorption decreases. This leads to a low plasma phosphate concentration, which stimulates the production of 1,25-dihydroxycholecalciferol and results in increased intestinal absorption of calcium; concurrently; it also causes hypercalciuria. The ingestion of sucrose and other simple sugars causes an exaggerated rise in the urinary calcium-oxalate content in approximately 70% of people with recurrent kidney stones.39 

Gut Flora Studies are beginning to find a correlation between the proper balance of intestinal flora and a lower risk of oxalate kidney stones. Oxalate homeostasis depends in part on the intestinal anaerobic bacterium Oxalobacter formigenes. It now appears that O. formigenes contributes to oxalic acid homeostasis and that its absence may predispose individuals to idiopathic calcium-oxalate kidney stone disease.39 This bacterium is found primarily in the colon, and its loss through prolonged, widespread use of antibiotics is associated with an increased risk of hyperoxaluria and calcium-oxalate stone formation.40 Studies in animals and human volunteers have indicated that, when administered therapeutically, O. formigenes can repopulate the gut and reduce the urinary oxalate concentration after an oxalate load, hence reducing the incidence of calcium-oxalate kidney stone formation.41 More recent human studies have developed showing an inverse correlation with O. formigenes colonization and recurrent nephrolithiasis, inflammatory bowel disease, and idiopathic calcium nephrolithiasis, thus suggesting this unique commensal may confer some protection against future kidney stone disease.42 

Nutrients

Magnesium and Vitamin B6

A magnesium-deficient diet accelerates the deposition of calcium in renal tubules in rats.43 Magnesium has been shown to increase the solubility of calcium oxalate and inhibit the precipitation of both calcium phosphate and calcium oxalate.44–46 A low ratio of urinary magnesium to calcium is an independent risk factor for stone formation.47 Supplemental magnesium alone has been shown to be effective in preventing recurrences of kidney stones. When magnesium is used in conjunction with vitamin B6, an even greater effect is noted.48,49 Pyridoxine is known to reduce the endogenous production and urinary excretion of oxalates,50,51 and patients with recurrent oxalate stones have abnormal activation levels of erythrocyte glutamate pyruvate transaminase, erythrocyte glutamicoxaloacetic transaminase (EGOT), urinary glutamic-pyruvic acid transaminase, and urinary glutamic-oxaloacetic transaminase, indicating clinical insufficiency of vitamin B6 as a cofactor and impaired glutamic acid synthesis. These levels return to normal after 3 months of treatment.51 Induced pyridoxine deficiency in rats has been shown to produce oxaluria and calcium-oxalate lithiasis (which is prevented by magnesium supplementation).50 Several studies have confirmed the benefits of vitamin B6 as a sole agent in reducing urine oxalate, albeit with a small population size. Doses between 200 to 500 mg have been shown to normalized hyperoxaluria in those with calcium-oxalate stones. However, other studies have questioned the benefit of B6 as a sole agent, with a large review

CHAPTER 191 

Kidney Stones

1523

BOX 191.1  Oxalate Content of Select Foods Vegetables High Oxalate, >10 mg per Serving Beets—greens or roota Celery Collards Dandelion greens Eggplant Escarole Green beans Kale Leeks Okrab Parsley Parsnips Peppers, green Potatoes Pumpkin Spinacha Squash, yellow summer Sweet potatoes Swiss charda Tomato sauce, canned Turnip greens Watercress  Moderate Oxalate, 10 mg per Serving Concord grapes Figs, driedb Kiwi

Lemon peel Lime peel Orange peel Rhubarba  Moderate Oxalate, 10 mg per Serving Bread, whole wheat Buckwheatc Oatmeal Popcorn Spelt Stone-ground flour Wheat bran Wheat germ Whole-wheat flour  Moderate Oxalate, 10 mg per Serving Garbanzo beans Lentils Soy and all soy products  Moderate Oxalate, 10 mg per Serving Almonds Brazil nuts Hazelnuts Peanuts Peanut butter Pecans Sesame seeds Sunflower seeds  Moderate Oxalate,